EP2164833A2 - Quinazolinamide derivatives - Google Patents

Quinazolinamide derivatives

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Publication number
EP2164833A2
EP2164833A2 EP08773474A EP08773474A EP2164833A2 EP 2164833 A2 EP2164833 A2 EP 2164833A2 EP 08773474 A EP08773474 A EP 08773474A EP 08773474 A EP08773474 A EP 08773474A EP 2164833 A2 EP2164833 A2 EP 2164833A2
Authority
EP
European Patent Office
Prior art keywords
conh
nha
benzyl
het
cooa
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP08773474A
Other languages
German (de)
French (fr)
Other versions
EP2164833B1 (en
Inventor
Hans-Michael Eggenweiler
Christian Sirrenberg
Hans-Peter Buchstaller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
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Merck Patent GmbH
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Publication of EP2164833A2 publication Critical patent/EP2164833A2/en
Application granted granted Critical
Publication of EP2164833B1 publication Critical patent/EP2164833B1/en
Not-in-force legal-status Critical Current
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
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Definitions

  • the invention had the object of finding new compounds with valuable properties, in particular those that can be used for the production of medicaments.
  • the present invention relates to compounds involving the inhibition, regulation and / or modulation of HSP90, pharmaceutical compositions containing these compounds and the use of the compounds for the treatment of
  • HSPs Heat Shock Proteins
  • HSPs heat shock proteins
  • HSPs protective mechanism of external stress have been over time other important chaperone functions for individual HSPs are also described under normal stress-free conditions. For example, various HSPs regulate the correct folding, intracellular localization and function, or the regulated degradation of a number of biologically important proteins of cells.
  • HSPs constitute a gene family of individual gene products whose cellular expression, function and localization differ in different cells. The designation and classification within the family is due to their molecular weight e.g. HSP27, HSP70, and HSP90.
  • HSPs are also considered of great importance in tumor diseases. There are e.g. Evidence that the expression of certain
  • HSPs are related to the stage of tumor progression (Martin et al., 2000; Conroy et al., 1996; Kawanishi et al., 1999;
  • HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG), a derivative of geldanamycin, is currently undergoing clinical trials.
  • HSP90 represents about 1-2% of the total cellular protein mass. It is usually present in the cell as a dimer and is associated with a variety of proteins, so-called co-chaperones (see, e.g., Pratt, 1997). HSP90 is essential for the vitality of cells (Young et al., 2001) and plays a key role in the response to cellular stress by interacting with many proteins whose native folding by external stress, e.g. Heat shock, to restore the original fold or prevent aggregation of the proteins (Smith et al., 1998).
  • HSP90 is important as a buffer against the effects of mutations, presumably by correcting for incorrect protein folding induced by the mutation (Rutherford and Lindquist, 1998).
  • HSP90 also has a regulatory significance. Under physiological conditions, HSP90, along with its endoplasmic reticulum homolog, GRP94, plays a role in the cell balance to ensure the conformational stability and maturation of various "serving" key proteins, which can be divided into three groups: steroid hormone receptors, sera / Thr or tyrosine kinases (eg ERBB2, RAF-1, CDK4 and LCK) and a
  • HSP90 human immunoglobulin sequence
  • cytosolic HSP90 ⁇ the inducible HSP90 ⁇ isoform
  • GRP94 the endoplasmic reticulum
  • HSP75 / TRAP1 the mitochondrial matrix
  • ERBB2 is a specific "serving" protein of GRP94 (Argon et al. 1999), while the type 1 receptor of tumor necrosis factor (TNFR1) or the retinoblastoma protein (Rb) were detected as "clients" of TRAP1 (Song ).
  • TNFR1 tumor necrosis factor
  • Rb retinoblastoma protein
  • HSP90 is involved in a number of complex interactions with a large number of "serving” proteins and regulatory proteins (Smith, 2001), although precise molecular details have yet to be clarified
  • HSP90 is an ATP-dependent molecular chaperone (Prodromou et al, 1997), with dimerization
  • HSP90 inhibitors were benzoquinone ansamycins with the compounds herbimycin A and 3 (3 geldanamycin), originally having been shown to reverse the malignant phenotype of fibroblasts induced by transformation with the v-Src oncogene was (Uehara et al., 1985).
  • geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17AAG) showed an unchanged property in the inhibition of HSP90, the degradation of "serving" proteins and antitumoral activity in
  • Radicicol a macrocyclic antibiotic, also demonstrated a revision of the v-Src and v-Ha-Ras-induced malignant phenotype of fibroblasts (Kwon et al 1992, Zhao et al, 1995). Radicicol downgrades one
  • Coumarin-type antibiotics are known to bind to the ATP binding site of the HSP90 homolog DNA gyrase in bacteria.
  • the coumarin, novobiocin binds to the carboxy-terminal end of HSP90, which is another site in HSP90 than the benzoquinone Ansamycins and Radicicol, which bind to the N-terminal end of HSP90 (Marcu et al., 2000b).
  • PU3 a purine-derived HSP90 inhibitor, the degradation of signaling proteins, e.g. ERBB2, are shown. PU3 causes cell cycle arrest and differentiation in breast cancer cell lines (Chiosis et al., 2001).
  • HSP90 By including HSP90 in the regulation of a large number of signaling pathways that are critically important to the phenotype of a tumor, and the discovery that certain natural products exert their biological effect by inhibiting the activity of HSP90, HSP90 is currently a new target for development of a tumor therapeutic (Neckers et al., 1999).
  • the main mechanism of action of geldanamycin, 17AAG, and radicicol involves the inhibition of binding of ATP to the ATP binding site at the N-terminal end of the protein and the consequent inhibition of the intrinsic ATPase activity of HSP90 (see, eg, Prodromou et al. 1997; Stebbins et al., 1997; Panaretou et al., 1998).
  • the inhibition of ATPase activity of HSP90 prevents the
  • Heterocomplexes that "serve" proteins via the ubiquitin-proteasome pathway of degradation see, eg, Neckers et al., 1999; Kelland et al., 1999) .Treating tumor cells with HSP90 inhibitors leads to the selective degradation of important proteins fundamental for processes such as cell proliferation, cell cycle regulation and apoptosis. These processes are often deregulated in tumors (see, eg, Hostein et al., 2001).
  • the present invention relates to compounds which inhibit, regulate and / or modulate HSP90, compositions containing these compounds, and methods for their use in the treatment of HSP90-related diseases, such as tumor diseases, viral diseases, e.g. Hepatitis B (Waxman, 2002); Immunosuppression in transplantations (Bijlmakers, 2000 and Yorgin, 2000); Inflammatory Diseases (Bucci, 2000) such as Rheumatoid Arthritis, Asthma, Multiple Sclerosis, Type 1 Diabetes, Lupus Erythematosus, Psoriasis and Inflammatory Bowel Disease; cystic
  • HSP90-related diseases such as tumor diseases, viral diseases, e.g. Hepatitis B (Waxman, 2002); Immunosuppression in transplantations (Bijlmakers, 2000 and Yorgin, 2000); Inflammatory Diseases (Bucci, 2000) such as Rheumatoid Arthritis, Asthma, Multiple Sclerosis, Type 1 Diabetes,
  • Hemangiomas, endometriosis and tumor angiogenesis Hemangiomas, endometriosis and tumor angiogenesis; infectious diseases; Autoimmune diseases; ischemia; Promotion of nerve regeneration (Rosen et al., WO 02/09696, Degranco et al., WO 99/51223, Gold, US 6,210,974 B1); fibrogenetic diseases, e.g. Scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis (Strehlow, WO 02/02123).
  • fibrogenetic diseases e.g. Scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis
  • the invention also relates to the use of the compounds of the invention for the protection of normal cells against toxicity caused by chemotherapy, as well as for use in diseases where protein misfolding or aggregation is a major causative factor, e.g. Scrapie, Creutzfeldt-Jakob Disease, Huntington or Alzheimer's
  • sarcoma or carcinoma selected from the group consisting of fibrosarcoma, myxosarcoma , Liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
  • Squamous cell carcinoma basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonic carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,
  • Medulloblastoma craniopharyngioma, ependymoma, pinealoma, hemangio- blastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma,
  • Neuroblastoma retinoblastoma, leukemia, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia and severe chain disease.
  • the viral pathogen is selected from the group consisting of hepatitis type A, type B hepatitis, type C hepatitis, influenza, varicella, adenovirus, herpes simplex type I (HSV-I), herpes Simplex type II (HSV-M), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV), papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackievirus, mumps virus,
  • WO 01/72779 further describes the use of the GRP94 modulation compounds therein, wherein the modulated GRP94 biological activity comprises an immune response in an individual, protein transport from the endoplasmic reticulum, recovery from hypoxic / anoxic stress, recovery from malnutrition, recovery of heat stress, or combinations thereof, and / or wherein the disorder is a type of cancer, an infectious disease, a disorder involving disturbed protein transport from the endoplasmic reticulum, ischemia / reperfusion disorder, or combinations thereof wherein the ischemia / reperfusion-associated disorder is a consequence of cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord injury, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm , Hypotension, hypoglycemia, status epilepticus,
  • Schizophrenia a neurodegenerative disorder, Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • neonatal stress Huntington's chorea, amyotrophic lateral sclerosis (ALS), or neonatal stress.
  • a medicament for altering a subsequent cellular response to an ischemic condition at a tissue site in an individual by treating the cells at the tissue site with the GRP94 protein modulator to enhance the GRP94 activity in cells to a subsequent cellular response an ischemic condition is changed, the subsequent ischemic condition preferably being the consequence of
  • Donor tissue for a transplant is.
  • the present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method of treatment said diseases comprising administering one or more of the compounds of the invention to a patient in need of such administration.
  • the host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs,
  • WO 03/041643 A2 discloses HSP90-inhibiting zearalanol derivatives.
  • HSP90-inhibiting indazole derivatives are known from WO 06/010595 and
  • a radicicol derivative, KF58333 inhibits expression of hypoxia-inducible factoM ⁇ and vascular endothelial growth factor, angiogenesis and growth of human breast cancer xenografts
  • J. Cancer Res. Vol. 92 (12), 1342-1351.
  • the invention relates to compounds of the formula
  • R 1 is H, A, (CH 2 ) nCONH 2 , (CH 2 ) n CONHA, (CH 2 ) n CONAA ⁇ Hal,
  • R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
  • A, A ' are each independently of one another unbranched or branched alkyl having 1-10 C atoms, in which 1-3 non-adjacent CH 2 groups are represented by O, S, SO, SO 2 , NH, NMe or NEt and / or 1 -5 H atoms can be replaced by F, OH and / or Cl,
  • Alk 1 cyclic alkyl having 3-8 C atoms or cycloalkylalkylene, in which 1-5 H atoms may be replaced by F, OH and / or Cl, Alk 1 alkenyl or alkynyl having 2-6 C atoms, m O, 1 or 2, n is O, 1, 2, 3 or 4, and their pharmaceutically usable derivatives, salts, solvates and
  • Stereoisomers including mixtures thereof in all ratios.
  • the invention relates to the compounds of formula I and their salts and to a process for the preparation of compounds of formula I and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, characterized in that
  • R 1 has the meaning given in claim 1, and LF, Cl, Br, I or a free or a reactively modified OH group,
  • the invention also relates to the stereoisomers (E, Z isomers) and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.
  • the term "effective amount” means the amount of a drug or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.
  • the term "therapeutically effective amount” means an amount that, as compared to a corresponding subject who has not received that amount, results in: improved treatment, cure, prevention or elimination of a disease, a clinical picture, a disease state, a disease, a disorder or side effects or the
  • Reduction of the progression of a disease, a disease or a disorder Reduction of the progression of a disease, a disease or a disorder.
  • terapéuticaally effective amount also includes the amounts effective to increase normal physiological function.
  • the invention also provides mixtures of the compounds of the formula I according to the invention, e.g. Mixtures of two diastereomers, e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
  • Carbamoyl means aminocarbonyl.
  • Boc or Boc means tert-butyloxycarbonyl.
  • a or A ' is preferably alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms.
  • a or A ' is particularly preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl or tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-
  • A, A ' also each independently represent unbranched or branched alkyl having 1-10 C atoms, in which 1-3 non-adjacent CH 2 groups have been replaced by O, S, SO, SO 2 , NH, NMe 1 or NEt can, such as 2-methoxy-ethyl or 3-methylamino-propyl.
  • a or A ' also means cyclic alkyl (cycloalkyl). Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cyclic alkyl furthermore preferably denotes cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl.
  • Cycloalkylalkylene means, for example, cyclopropylmethylene or cyclohexylmethy len.
  • a or A ' also means Alk 1 .
  • Alk 1 is alkenyl having 2-6 C atoms, such as vinyl or propenyl.
  • Alk 1 also means alkynyl such as ethynyl.
  • n is preferably 0, 1 or 2.
  • R 2 is preferably H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2- (pyridin-2-ylamino) ethyl or benzyl.
  • R 3 is preferably methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl, furyl-2-ylmethyl, HC ⁇ C-CH 2 -, 2-methoxy-ethyl, 3-trifluoromethyl- 46
  • 2-methylsulfanilethyl 2-hydroxy-2-phenylethyl, 2- (N-ethyl-N-methylamino) ethyl, 2-diethylaminoethyl, 1-methyl-1H-pyrazol-3-yl, Quinoline-5- or 8-yl, 2-methylsulfanil-phenyl, biphenyl-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 2- (1H-benzimidazol-2-yl) - phenyl, 3,4,5-trimethoxyphenyl, 2-ethynylphenyl or 1-methyl-5-trifluoromethyl-1H-indazol-3-yl.
  • Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert
  • the heterocyclic radicals may also be partially or completely hydrogenated. Het can so z.
  • B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-, -3-, -4- or -5- pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrroli- 5-dinyl, tetrahydro-1-, - 2- or 4-imidazolyl, 2,3-dihydro-1-, 2-, -3-, -4- or
  • a g is 6-, 7- or 8-3,4-dihydro-2H-benzo [1,4] oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4- Ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxomethylenedioxy) -phenyl or else 3,4-
  • Het is preferably unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S (O) m A, Hal, NO 2 , CN, COA, CHO,
  • the heterocyclic radicals may also be partially or completely hydrogenated.
  • B. also mean 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or 5-furyl, tetrahydro-2 - or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-, -3-, -4- or -5- pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2 - or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -A- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4 Di
  • Het 1 particularly preferably denotes pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, benzimidazolyl, morpholinyl, pyrimidinyl which is unsubstituted or mono-, di- or trisubstituted by A, OA, OH 1 Hal, CN and / or OO (carbonyl oxygen) , Piperidinyl, pyrrolidinyl or piperazinyl.
  • the compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms.
  • Formula I encompasses all these forms.
  • Partial formulas Ia to Ii are expressed which correspond to the formula I and wherein the unspecified radicals corresponding to those given in formula I.
  • NHSO 2 A and / or 0 (carbonyl oxygen) substituted pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,
  • Benzimidazolyl indazolyl, indolyl, 1, 3-dihydro- isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzo [1,3] dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, pyrrolidinyl or piperidinyl; 5 in Ib Het 1 unsubstituted or one, two or three times by A,
  • Ic A 1 A are each independently of one another unbranched or branched alkyl having 1-6 C atoms, in which 1-2 CH 2 - groups by O, NH and / or NMe and / or also 1-5 H-atoms by F , OH and / or Cl can be replaced, or
  • R 2 is H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2
  • 1H-pyrazol-4-ylmethyl 2-methylsulfanil-ethyl, 2-hydroxy-2-phenyl-ethyl, 2- (N-ethyl-N-methyl-amino) -ethyl, 2-diethylamino-ethyl, 1-methyl- 1H-pyrazol-3-yl, 5-quinolin-5 or 8-yl, 2-methylsulfanil-phenyl, biphenyl
  • Ih R 1 is H, A, (CH 2 ) n CONH 2 , (CH 2 ) n CONHA, (CH 2 ) n CONAA ',
  • R 2 is H, A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NHHet, (CH 2 ) n SA or (CH 2 ) n CH (OH) Ar, R 3 A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n CN, (CH 2 ) n NH 2 , (CH 2 ) n NHA, ( CH 2 ) RNAA 1 , (CH 2 ) n OH, (CH 2 ) n OA or
  • R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NH 2 , (CH 2 ) n NHA or (CHz) n NAA 1 ,
  • Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, (CH 2 ) n OA, (CH 2 ) n OH, (CH 2 ) n CN, SA, SOA, SO 2 A, NO 2 , C ⁇ CH, (CH 2 ) n COOH, CHO, (CH 2 ) n COOA, CONH 2 , CONHA, CONAA 1 , NHCOA,
  • CONHAr 1 CONH (CH 2 ) n COOA, CONH (CH 2 ) n COOH, NHCO (CH 2 ) n COOA, NHCO (CH 2 ) n COOH, CONH (CH 2 ) n NH 2 , CONH (CH 2 ) n NHA, CONH (CH 2 ) O, NAA 1 , CONH (CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and / or (CH 2 ) n CH (NH 2 ) COOH substituted phenyl, naphthyl, tetrahydronaphthyl or biphenyl, Ar 1 is unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl, substituted by A, Hal and / or OA, H is unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (
  • COA CHO, COOA, COOBenzyl, CONH 2 , CONHA, CONAA 1 , SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA ⁇ NHSO 2 A and / or O (carbonyl oxygen) substituted pyridyl, pyrimidinyl, furyl, thienyl,
  • Het 1 is unsubstituted or mono-, di- or trisubstituted by A,
  • OA, OH, Hal, CN and / or O (carbonyl oxygen) substituted pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, benzimidazolyl, triazolyl, morpholinyl, pyrimidinyl, piperidinyl, pyrrolidinyl or piperazinyl,
  • A, A ' are each independently unbranched or branched Alkyl having 1-6 C atoms, in which 1-2 CH 2 groups may be replaced by O, NH and / or NMe and / or also 1-5 H atoms by F, OH and / or Cl, or the cyclic one Alkyl having 3-8 C atoms, wherein 1-3 H atoms may be replaced by OH, m is O, 1 or 2, n is O, 1 or 2 ,. , , mean; R 1 H, A 1 (CH 2 ) n CONH 2 , (CH 2 ) n CONHA,
  • R 2 is H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2
  • R 3 is methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl, furyl-2-ylmethyl, HC ⁇ C-CH 2 -, 2-methoxy-ethyl, 3
  • Morpholin-4-yl-ethoxy) -benzyl 4- (triazol-1-yl) -benzyl, 3- (morpholin-4-yl) -benzyl, 3- (pyrimidin-5-yl) -benzyl, 3- ( Morpholin-4-ylmethyl) benzyl, cyclopropylmethyl, 2-cyanoethyl, 2-dimethylamino-ethyl, cyclohexyl, 3-or
  • R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
  • A, A ' are each independently of one another unbranched or branched alkyl having 1-6 C atoms, in which 1-2 CH 2 - groups by O, NH and / or NMe and / or also 1-5
  • H atoms may be replaced by F, OH and / or Cl, or cyclic alkyl having 3-8 C atoms, in which 1-3 H atoms may be replaced by OH, m is 0, 1 or 2, n is 0, 1 or 2, mean; and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including mixtures thereof in all ratios.
  • the starting materials can, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of the invention.
  • the starting compounds are generally known. If they are new, they can be produced by methods known per se.
  • Compounds of the formula I can preferably be obtained by reacting a compound of the formula II with a compound of the formula III.
  • L is preferably F, Cl, Br, I or a free or a reactively modified OH group, e.g. an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyl-oxy).
  • L is preferably Cl.
  • the reaction is usually carried out in an inert solvent, in
  • an acid-binding agent preferably an alkali or
  • Alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals preferably of potassium, sodium, calcium or cesium.
  • a weak acid of the alkali or alkaline earth metals preferably of potassium, sodium, calcium or cesium.
  • organic base such as triethylamine, dimethylaniline, pyridine or quinoline may be beneficial.
  • a coupling reagent e.g. Ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate or propanephosphonic acid cycloanhydride.
  • reaction is carried out by methods known to the person skilled in the art.
  • reaction takes place in a suitable solvent.
  • suitable solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or
  • dichloromethane Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; 0 amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate
  • Particularly preferred solvents are acetonitrile or DMF.
  • the reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about 0 ° 0 and 150 °, usually between 15 ° and 120 °, more preferably between 50 ° and 100 0 C.
  • a compound of the formula I into another compound of the formula I by converting a radical R 1 into another radical R 1 , for example by reacting nitro groups, for example by hydrogenation on Raney nickel or Pd -Cool in an inert solvent such as methanol or ethanol, reduced to amino groups 0 and / or converts an ester group into a carboxy group and / or converts an aldehyde group by reductive amination in an alkylated amine and / or
  • Acid chlorides are converted by reaction with an amine in an acid amide.
  • free amino and / or hydroxy groups may be acylated in the usual manner with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, conveniently in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine Temperatures between -60 and + 30 °.
  • Ether cleavages are carried out by methods known to those skilled in the art.
  • the reaction is carried out in a suitable solvent as indicated above, preferably by the addition of boron tribromide.
  • the reaction is most preferably carried out in dichloromethane at a reaction temperature between about -30 ° and 50 °, normally between -20 ° and 20 °, more preferably between about -15 ° and about 0 °.
  • the invention therefore also relates to the compounds of the formula IV
  • R 1 is H, A, (CH 3) n CONH 2 , (CH 2 ) n CONHA, (CH 2 ) H CONAA 1 , Hal,
  • R 4 , R 5 are each independently (CH 2 ) n OH, ( CH 2 ) n OA,
  • Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, (CH 2 ) n OA, (CH 2 ) n OH, (CHz) n CN, SA, SOA, SO 2 A, NO 2 , C ⁇ CH, (CH 2 ) n COOH, CHO, (CH 2 ) n COOA,
  • NHCO (CHz) n COOA NHCO (CHz) n COOH 1 CONH (CHz) n NH 2 , CONH (CHz) n NHA, CONH (CHz) n NAA 1 , CONH (CHz) n CN, NHCOHet, SO 2 Het, COHet and / or (CHz) n CH (NH 2 ) COOH substituted phenyl, naphthyl, tetrahydronaphthyl or
  • Ar 1 is unsubstituted or mono-, di-, tri-, tetra- or quintuply phenyl substituted by A, Hal and / or OA
  • Atoms that are unsubstituted or one or two times A are unsubstituted or one or two times A
  • Cycloalkylalkylene in which 1-5 H atoms may be replaced by F 1 OH and / or Cl, Alk 1 is alkenyl or alkynyl having 2-6 C atoms, m is O, 1 or 2,
  • 20 n is 0, 1, 2, 3 or 4, and their salts.
  • R 1 is H, A, (CH 2 ) n CONH 2 , (CH 2 ) n CONHA, (CH 2 ) n CONAA ', Hal,
  • CH CH-COOA, CH 2 CH (OH) CH 2 OH, O (CH 2 ) n OH, NH (CH 2 ) n OH,
  • R 2 is H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2- (pyridine)
  • R 3 is methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl, furyl
  • Piperazinyl, piperidinyl or morpholinyl, R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
  • Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, (CH 2 ) n OA, (CH 2 ) n OH, (CH 2 ) n CN, SA, SOA, SO 2 A, NO 2 , C ⁇ CH, (CH 2 ) n COOH, CHO, (CH 2 ) n COOA, CONH 2 , CONHA, CONAA 1 , NHCOA, CH (OH) A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) RNAA 1 , (CH 2 ) n NAAr 1 , O (CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO (CH 2 ) n Ar 1 , (CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 , O (CH 2 ) n Ar 1 , SO 2
  • NHCO (CH 2 ) n COOA NHCO (CH 2 ) n COOH, CONH (CH 2 ) n NH 2 , CONH (CH 2 ) n NHA, CONH (CH 2 ) n NAA ', CONH (CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and / or (CH 2 J n CH (NH 2 ) COOH substituted phenyl, naphthyl, tetrahydronaphthyl or
  • Ar 1 is unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl substituted by A, Hal and / or OA
  • H is unsubstituted or mono-, di- or trisubstituted by Hal
  • Triazolyl Triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl,
  • Het 1 unsubstituted or simply by 0 (carbonyl oxygen) substituted morpholinyl, piperidinyl or pyrrolidinyl, A, A 'each independently of one another unbranched or branched alkyl having 1-6 C atoms, wherein 1-2 CH 2 groups by O, NH and or NMe and / or 1-5 H atoms may be replaced by F, OH and / or Cl, or cyclic alkyl having 3-8 C atoms, wherein 1-3 H atoms by
  • OH can be replaced, m is 0, 1 or 2, n is 0, 1 or 2, and their salts. 5
  • Containing carboxylic acid group one of their suitable salts can be formed by reacting the compound with a suitable base to the corresponding base addition salt.
  • bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide
  • Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide
  • Alkali metal alcoholates e.g. Potassium ethanolate and sodium propanolate
  • various organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride,
  • 35 corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and 46
  • Benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like.
  • pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate,
  • Galacterate from mucic acid
  • galacturonate glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, Maleate, malonate, mandelate, metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.
  • the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium -
  • Sodium and zinc salts but this is not intended to be limiting.
  • Preferred among the above salts are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium.
  • Compounds derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, e.g. Arginine, betaine, caffeine, chloroprocaine, choline,
  • N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, Diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine,
  • Lysine meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine,
  • Polyamine resins procaine, purines, theobromine, triethanolamine,
  • Triethylamine trimethylamine, tripropylamine and tris (hydroxymethyl) - methylamine (tromethamine), but this is not intended to be limiting.
  • Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C 4 ) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -C 4 ) alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C 10 - C 8) alkyl halides, for example Decyh dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl- (C 1 -C 4 ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize. With such salts, both water-soluble and oil-soluble according to the invention
  • Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, Sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, which is not intended to be limiting.
  • the acid addition salts of basic compounds of this invention are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner.
  • the free base can be determined by
  • the pharmaceutically acceptable base addition salts of the compounds of the invention are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
  • metals are sodium, potassium, magnesium and calcium.
  • Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
  • the base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner.
  • the free acid can be passed through
  • the 30 invention also encompasses multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
  • the pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the body.
  • Compounds of the invention may be chiral due to their molecular structure and accordingly may occur in various enantiomeric forms. They may therefore be in racemic or optically active form.
  • the pharmaceutical activity of the racemates or of the stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers.
  • the end product or else the intermediates may already be separated into enantiomeric compounds, chemical or physical measures known to those skilled in the art, or already be used as such in the synthesis.
  • Suitable release agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulphonylproline) or the different optically active camphorsulfonic acids.
  • optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulphonylproline) or the different optically active camphorsulfonic acids.
  • a chromatographic separation of enantiomers by means of an optically active separation by means of (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or silica-gel-fixed chirally derivatized methacrylate polymers).
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile, for example in the ratio 82: 15: 3.
  • the invention further provides the use of the compounds and / or their physiologically acceptable salts for the preparation of a pharmaceutical preparation (pharmaceutical preparation), in particular by a non-chemical route.
  • a pharmaceutical preparation pharmaceutical preparation
  • they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or excipient and optionally in combination with one or more further active ingredients.
  • the invention furthermore relates to medicaments comprising at least one compound according to the invention and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
  • compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
  • a moiety may contain, for example, from 0.1 mg to 3 g, preferably from 1 mg to 700 mg, more preferably from 5 mg to 100 mg of a compound of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
  • Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof Active ingredient included.
  • such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
  • compositions may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal). Ways, adapt.
  • Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).
  • compositions adapted for oral administration may be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active ingredient component in the case of oral administration in the form of a tablet or capsule, can be mixed with an oral, non-toxic and pharmaceutically acceptable inert carrier, e.g. Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as
  • Starch or mannitol is mixed.
  • a flavor, preservative, dispersant and dye may also be present.
  • Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
  • Lubricants and lubricants such as highly disperse silica, talc,
  • Magnesium stearate, calcium stearate or polyethylene glycol in solid form 5 can be added to the powder mixture before the filling process.
  • Disintegrants or solubilizers e.g. Agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
  • Suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture.
  • suitable binders include starch,
  • c gelatin natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc.
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate , Magnesium stearate, sodium
  • the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the tablets are formulated by, for example, preparing a powder mixture, granulating or drying
  • a powder mixture is prepared by treating the appropriately comminuted compound with a diluent or base as described above, and
  • a binder such as, for example, carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone
  • a dissolution initiator for example paraffin
  • a absorption accelerator for example a quaternary salt and / or an absorbent, for example bentonite
  • 35 granulate by mixing it with a binder, such as syrup, starch paste, Acadia slime or solutions of cellulose or polymer wetted material and pressed through a sieve.
  • a binder such as syrup, starch paste, Acadia slime or solutions of cellulose or polymer wetted material and pressed through a sieve.
  • the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are formed in
  • Granules are broken up.
  • the granules may be greased by addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds.
  • the greased mixture is then compressed into tablets.
  • the compounds of the invention can also be used with a free-flowing inert
  • a transparent or opaque protective layer consisting of a shellac seal, a layer of sugar or polymer
  • ⁇ 5 material and a gloss layer of wax may be present.
  • Dyes can be added to these coatings in order to differentiate between different dosage units.
  • Oral fluids e.g. Solution, syrups and elixirs, can be in shape
  • Syrups can be made by dissolving the compound in an appropriate taste aqueous solution while using elixirs
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,
  • flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, among others, may also be added.
  • the formulation can also be prepared so that the release is prolonged or retarded For example, by coating or embedding particulate material in polymers, wax, etc.
  • Liposome delivery systems such as e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be prepared from various phospholipids, such as e.g. Cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the invention as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds can also be coupled with soluble polymers as targeted drug carriers.
  • Such polymers may include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol,
  • Polyhydroxyethylaspartamidphenol or polyethylene oxide polylysine substituted with Palmitoylresten include.
  • the compounds can be attached to a class of biodegradable polymers suitable for the controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyano-acrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • Formulations may be presented as discrete plasters for prolonged, intimate contact with the epidermis of the recipient.
  • the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration may be used as ointments, creams, suspensions, lotions, powders, solutions,
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient can be used with either a paraffinic or water miscible cream base.
  • the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
  • the pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical application in the mouth include lozenges, troches and mouthwashes.
  • compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
  • Formulations in which the vehicle is a solid include a coarse powder having a particle size, for example in the range of
  • Suitable formulations for administration as a nasal spray or Nasal drops containing a liquid carrier include drug solutions in water or oil.
  • Formulations include fine particulate dusts or mists that can be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.
  • Formulations may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the subject
  • Recipient is included; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
  • the formulations may be administered in single or multiple dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use.
  • sterile carrier liquid e.g. Water for injections
  • formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration
  • a therapeutically effective amount of a compound of the present invention will depend on a number of factors, including, for example, the age and weight of the human or animal, the exact disease condition requiring treatment, and its severity
  • an effective amount of a compound of the invention for treatment is generally in the range of 0.1 to 100 mg / kg of body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg of body weight per day.
  • the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same.
  • An effective amount of a salt or solvate or a physiologically functional derivative thereof may be mentioned as
  • Proportion of the effective amount of the compound according to the invention can be determined per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
  • the invention furthermore relates to medicaments comprising at least one compound according to the invention and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further active pharmaceutical ingredient.
  • chemotherapeutic agents are preferred, in particular those which inhibit angiogenesis and thereby the
  • VEGF receptor inhibitors including robozymes and antisense, which are directed to VEGF receptors, as well as angiostatin and endostatin.
  • antineoplastic agents that can be used in combination with the compounds of the invention generally include alkylating agents, antimetabolites; Epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor;
  • procarbazine Mitoxantrone or platinum coordination complexes.
  • Antineoplastic agents are preferably selected from the following classes:
  • Anthracyclines vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolides, pteridines, diynes, and
  • Mitomycin C porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine,
  • Cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives e.g.
  • Etoposide, Etoposide Phosphate or Teniposide Melphalan, Vinblastine, Vincristine, Leursidine, Vindesine, Leursine and Paclitaxel.
  • Other preferred antineoplastic agents are selected from the group estramustins, carboplatin, cyclophosphamide, bleomycin, gemcitabine, ifosamide, melphalan, hexamethylmelamine, thiotepa, cytarabine, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, arabinosyl-cytosine , Bicalutamide, Flutamide, Leuprolide, Pyridobenzoindole derivatives, Interferons and Interleukins.
  • the invention is also a set (kit), consisting of separate packages of
  • the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
  • suitable containers such as boxes or boxes, individual bottles, bags or ampoules.
  • the set may e.g. separate ampoules containing, in each case, an effective amount of a
  • the present compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment of diseases in which HSP90 plays a role.
  • the invention thus relates to the use of the compounds according to the invention and their pharmaceutically usable compounds
  • the present invention includes the use of the compounds of the invention and / or their physiologically acceptable
  • Tumor diseases such as fibrosarcoma, myxosarcoma, liposarcoma, Chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiosarcoma, rhabdomyosarcoma,
  • Colon carcinoma pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
  • Squamous cell carcinoma basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma,
  • choriocarcinoma 10 choriocarcinoma, seminoma, embryonic carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangio-
  • ⁇ c blastoma acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia and severe chain disease; viral diseases, wherein the viral pathogen is selected from the
  • hepatitis type A Group consisting of hepatitis type A, type B hepatitis, type C hepatitis, 0
  • HSV-I herpes simplex type I
  • HSV-II Simplex type II
  • rinderpest rinderpest
  • rhinovirus echovirus
  • rotavirus rotavirus
  • respiratory syncytial virus RSV
  • papillomavirus papovavirus
  • cytomegalovirus echinovirus
  • arbovirus huntavirus
  • coxsackievirus coxsackievirus
  • HIV-I human immunodeficiency virus type I
  • HAV-II human immunodeficiency virus type II
  • 3Q Diseases such as Rheumatoid Arthritis, Asthma, Sepsis, Multiple Sclerosis, Type 1 Diabetes, Lupus Erythematosus, Psoriasis and Inflammatory Bowel Disease; Cystic fibrosis; Diseases associated with angiogenesis such as diabetic retinopathy,
  • fibrogenetic disorders such as Scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis;
  • the compounds according to the invention can in particular the
  • the present invention further comprises the use of the compounds of the invention and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the protection of normal cells against toxicity caused by chemotherapy, as well as for the treatment of diseases, wherein protein misfolding or aggregation is a major causal factor, such as Scrapie, Creutzfeldt-Jakob Disease, Huntington or Alzheimer's.
  • the invention also relates to the use of the invention
  • the invention also relates to the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the production of a medicament for HSP90 modulation, wherein the modulated HSP90 biological activity comprises an immune reaction in an individual, endoplasmic reticulum protein transport, recovery from hypoxic / anoxic stress, recovery from malnutrition, recovery from heat stress, or combinations thereof, and / or wherein the
  • Disorder is a type of cancer, an infectious disease that is associated with a disrupted protein transport from the endoplasmic reticulum, a
  • ischemia / reperfusion-associated disorder is a consequence of cardiac arrest, asystole and delayed ventricular arrhythmias, heart surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord injury, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm, hypotension, hypoglycemia, Status epilepticus, epileptic seizure, anxiety, schizophrenia, neurodegenerative disorder, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), or neonatal stress.
  • ALS amyotrophic lateral sclerosis
  • the invention also relates to the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the preparation of a medicament for treating ischemia as a result of cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, Spinal cord injury, head trauma, stroke, thromboembolic stroke, haemorrhagic stroke, cerebral vasospasm, hypotension,
  • hypoglycemia status epilepticus, an epileptic seizure, anxiety, schizophrenia, a neurodegenerative disorder, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), or neonatal stress.
  • ALS amyotrophic lateral sclerosis
  • geldanamycin or 17-allylamino-17-demethoxy-geldanamycin (17AAG) and their competitive inhibition to HSP90 can be used to determine the inhibitory activity of the compounds of the invention (Carreras et al., 2003, Chiosis et al., 2002).
  • Radioligand is thereby tritiated 17-allylamino-geldanamycin, [3H] 17AAG, used.
  • This filter binding assay allows a targeted search for inhibitors that interfere with the ATP binding site.
  • Recombinant human HSP90 ⁇ (expressing E. coli, 95% purity); [3H] 17AAG (17-allylamino-geldanamycin, [allylamino-2,3- 3 H. Specific activity: 1, 11x10 12 Bq / mmol (Moravek, MT-1717); HEPES filter buffer (50 mM HEPES, pH 7.0 , 5mM MgCl2, BSA 0.01%) Multiscreen FB (1 ⁇ m) filter plate (Millipore, MAFBNOB 50).
  • the 96 well microtiter filter plates are first watered and coated with 0.1% polyethyleneimine.
  • the test is carried out under the following conditions:
  • HSP90 1, 5 ⁇ g / assay
  • the supernatant in the filter plate is aspirated using a vacuum manifold (Millipore Multiscreen Separation System) and the filter washed twice.
  • the filter plates are then measured in a beta counter (Microbeta, Wallac) with scintillator (Microscint 20, Packard). From the “counts per minutes” values "% of control" is determined and from this the IC-50 value of a connection is calculated.
  • “usual workup” means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracting with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization.
  • Ion source electrospray (positive mode); Scan: 100-1000 m / z;
  • Fragmentation voltage 60 V; Gas temperature: 300 0 C, DAD: 220 nm.
  • Solvent LiChrosolv grade from Merck KGaA Solvent A: H2O (0.01% TFA) Solvent B: ACN (0.008% TFA)
  • Triethylamine 15.15 mg of palladium (II) acetate, 20.55 mg of tris-o-toylamine and 4 ml of acetonitrile is irradiated under argon atmosphere for 30 minutes at 120 ° in the microwave. It is poured into water and extracted with dichloromethane. It is dried and the solvent is removed. The residue is taken up in a little acetonitrile. The product precipitates under ultrasound irradiation. This gives 196.5 mg "A142"
  • the cleavage of the trimethylsilyl group is carried out by stirring 15 mg of "A146" in 2 ml of THF and 4.47 ⁇ l of KOH (47%). It is poured into water and extracted with ethyl acetate. After usual workup, 12 mg of 2-amino-6- (prop-1-ynyl) -4- (1, 3-dihydro-isoindol-2-yl-carbonyl) quinazoline
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 2 l of twice-distilled water with 2N hydrochloric acid, filtered sterile, filled into injection vials, lyophilized under sterile conditions and closed under sterile conditions. Each injection jar contains 5 mg of active ingredient.
  • Example B Suppositories A mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • 500 mg of an active ingredient according to the invention are mixed with 99.5 g of Vaseline under aseptic conditions.
  • Example E tablets are pressed, which are then in the usual
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of an active ingredient according to the invention in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

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Abstract

The invention relates to novel quinazolinamide derivatives of formula (I) wherein R1 - R3 have the meanings cited in claim 1. Said derivatives are HSP90 inhibitors and can be used to produce a medicament for treating diseases, in which the inhibition, regulation and/or modulation of HSP90 plays a part.

Description

Chinazolinamidderivate Chinazolinamidderivate
HINTERGRUND DER ERFINDUNGBACKGROUND OF THE INVENTION
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollen Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können.The invention had the object of finding new compounds with valuable properties, in particular those that can be used for the production of medicaments.
Die vorliegende Erfindung betrifft Verbindungen, bei denen die Hemmung, Regulierung und/oder Modulation von HSP90 eine Rolle spielt, ferner pharmazeutische Zusammensetzungen, die diese Verbindungen enthalten, sowie die Verwendung der Verbindungen zur Behandlung vonThe present invention relates to compounds involving the inhibition, regulation and / or modulation of HSP90, pharmaceutical compositions containing these compounds and the use of the compounds for the treatment of
Krankheiten, bei denen HSP90 eine Rolle spielt.Diseases in which HSP90 plays a role.
Die korrekte Faltung und Konformation von Proteinen in Zellen wird durch molekulare Chaperone gewährleistet und ist kritisch für die Regulation des Gleichgewichts zwischen Protein Synthese und Degradation. Chaperone sind wichtig für die Regulation vieler zentraler Funktionen von Zellen wie z.B. Zeilproliferation und Apoptose (JoIIy and Morimoto, 2000; Smith et al., 1998; Smith, 2001).The correct folding and conformation of proteins in cells is ensured by molecular chaperones and is critical for the regulation of the balance between protein synthesis and degradation. Chaperones are important for the regulation of many central functions of cells, e.g. Cell proliferation and apoptosis (Joill and Morimoto, 2000; Smith et al., 1998; Smith, 2001).
Hitzeschock-Proteine (heat shock proteins, HSPs) Die Zellen eines Gewebes reagieren auf äußerlichen Stress wie z.B.Heat Shock Proteins (HSPs) The cells of a tissue respond to external stress, e.g.
Hitze, Hypoxie, oxidativem Stress, oder Giftstoffen wie Schwermetallen oder Alkoholen mit der Aktivierung einer Reihe von Chaperonen, welche unter der Bezeichnung „heat shock proteins" (HSPs) bekannt sind. Die Aktivierung von HSPs schützt die Zelle gegen Verletzungen, die durch solche Stressfaktoren ausgelöst werden, beschleunigt die Wiederherstellung des physiologischen Zustands und führt zu einem stresstoleranten Zustand der Zelle.Heat, hypoxia, oxidative stress, or toxins such as heavy metals or alcohols with the activation of a number of chaperones known as "heat shock proteins" (HSPs) .The activation of HSPs protects the cell against injuries caused by such stressors triggers the restoration of the physiological state and leads to a stress-tolerant state of the cell.
Neben diesem ursprünglich entdeckten durch HSPs vermitteltenIn addition to this originally discovered by HSPs mediated
Schutzmechanismus bei äußerlichem Stress wurden im Laufe der Zeit weitere wichtige Chaperon-Funktionen für einzelne HSPs auch unter normalen stressfreien Bedingungen beschrieben. So regulieren verschiedene HSPs beispielsweise die korrekte Faltung, die intrazelluläre Lokalisierung und Funktion oder den geregelten Abbau einer Reihe biologisch wichtiger Proteine von Zellen.Protective mechanism of external stress have been over time other important chaperone functions for individual HSPs are also described under normal stress-free conditions. For example, various HSPs regulate the correct folding, intracellular localization and function, or the regulated degradation of a number of biologically important proteins of cells.
HSPs bilden eine Genfamilie mit individuellen Genprodukten, deren Zellulärexpression, Funktion und Lokalisierung in verschiedenen Zellen sich unterscheidet. Die Benennung und Einteilung innerhalb der Familie erfolgt aufgrund ihres Molekulargewichts z.B. HSP27, HSP70, and HSP90.HSPs constitute a gene family of individual gene products whose cellular expression, function and localization differ in different cells. The designation and classification within the family is due to their molecular weight e.g. HSP27, HSP70, and HSP90.
Einigen menschlichen Krankheiten liegt eine falsche Proteinfaltung zugrunde (siehe Review z.B. Tytell et al., 2001; Smith et al., 1998). DieSome human diseases are based on incorrect protein folding (see review, e.g., Tytell et al., 2001; Smith et al., 1998). The
Entwicklung von Therapien, welche in den Mechanismus der Chaperon abhängigen Proteinfaltung eingreift, könnte daher in solchen Fällen nützlich sein. Beispielsweise führen bei der Alzheimer-Erkrankung, Prionenerkrankungen oder dem Huntington Syndrom falsch gefaltete Proteine zu einer Aggregation von Protein mit neurodegenerativem Verlauf. Durch falsche Proteinfaltung kann auch ein Verlust der Wildtyp- Funktion entstehen, der eine fehlregulierte molekulare und physiologische Funktion zur Folge haben kann.Development of therapies that interfere with the mechanism of chaperone-dependent protein folding might therefore be useful in such cases. For example, in Alzheimer's disease, prion diseases or Huntington's syndrome, misfolded proteins aggregate protein with a neurodegenerative course. Incorrect protein folding may also result in a loss of wild-type function, which may result in a misregulated molecular and physiological function.
HSPs wird auch eine grosse Bedeutung bei Tumorerkrankungen beigemessen. Es gibt z.B. Hinweise, dass die Expression bestimmterHSPs are also considered of great importance in tumor diseases. There are e.g. Evidence that the expression of certain
HSPs im Zusammenhang mit dem Stadium der Progression von Tumoren steht (Martin et al., 2000; Conroy et al., 1996; Kawanishi et al., 1999;HSPs are related to the stage of tumor progression (Martin et al., 2000; Conroy et al., 1996; Kawanishi et al., 1999;
Jameel et al., 1992; Hoang et al., 2000; Lebeau et al., 1991).Jameel et al., 1992; Hoang et al., 2000; Lebeau et al., 1991).
Die Tatsache, dass HSP90 bei mehreren zentralen onkogenenThe fact that HSP90 is involved in several central oncogenic
Signalwegen in der Zelle eine Rolle spielt und gewisse Naturstoffe mit krebshemmender Aktivität HSP90 targetieren, führte zu dem Konzept, dass eine Hemmung der Funktion von HSP90 bei der Behandlung von Tumorerkrankungen sinnvoll wäre. Ein HSP90 Inhibitor, 17- Allylamino-17-demethoxygeldanamycin (17AAG), ein Derivat von Geldanamycin, befindet sich gegenwärtig in klinischer Prüfung.Signaling pathways in the cell and targeting certain natural products with anticancer activity to HSP90 led to the concept that inhibition of HSP90 function would be useful in the treatment of tumor disease. An HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17AAG), a derivative of geldanamycin, is currently undergoing clinical trials.
HSP90HSP90
HSP90 repräsentiert ungefähr 1-2% der gesamten zellulären Proteinmasse. Es liegt in der Zelle gewöhnlich als Dimer vor und ist mit einer Vielzahl von Proteinen, sogenannten Co-chaperonen assoziiert (siehe z.B. Pratt, 1997). HSP90 ist essentiell für die Vitalität von Zellen (Young et al., 2001) und spielt eine Schlüsselrolle in der Antwort auf zellulären Stress durch Interaktion mit vielen Proteinen, deren native Faltung durch äußerlichen Stress, wie z.B. Hitzeschock, verändert wurde, um die ursprüngliche Faltung wiederherzustellen oder die Aggregation der Proteine zu verhindern (Smith et al.,1998).HSP90 represents about 1-2% of the total cellular protein mass. It is usually present in the cell as a dimer and is associated with a variety of proteins, so-called co-chaperones (see, e.g., Pratt, 1997). HSP90 is essential for the vitality of cells (Young et al., 2001) and plays a key role in the response to cellular stress by interacting with many proteins whose native folding by external stress, e.g. Heat shock, to restore the original fold or prevent aggregation of the proteins (Smith et al., 1998).
Es gibt auch Hinweise, dass HSP90 als Puffer gegen die Auswirkungen von Mutationen eine Bedeutung hat, vermutlich durch die Korrektur falscher Proteinfaltung, die durch die Mutation hervorgerufen wurde (Rutherford and Lindquist, 1998).There is also evidence that HSP90 is important as a buffer against the effects of mutations, presumably by correcting for incorrect protein folding induced by the mutation (Rutherford and Lindquist, 1998).
Darüber hinaus hat HSP90 auch eine regulatorische Bedeutung. Unter physiologischen Bedingungen spielt HSP90, zusammen mit seinem Homolog im Endoplasmatischen Retikulum, GRP94, eine Rolle im Zellhaushalt, um die Stabilität der Konformation und Reifung verschiedener „dient" Schlüsselproteine zu gewährleisten. Diese können in drei Gruppen unterteilt werden: Rezeptoren für Steroidhormone, Ser/Thr or Tyrosinkinasen (z.B. ERBB2, RAF-1 , CDK4 und LCK) und einerIn addition, HSP90 also has a regulatory significance. Under physiological conditions, HSP90, along with its endoplasmic reticulum homolog, GRP94, plays a role in the cell balance to ensure the conformational stability and maturation of various "serving" key proteins, which can be divided into three groups: steroid hormone receptors, sera / Thr or tyrosine kinases (eg ERBB2, RAF-1, CDK4 and LCK) and a
Sammlung unterschiedlicher Proteine wie z.B. mutiertes p53 oder die katalytische Untereinheit der Telomerase hTERT. Jedes dieser Proteine nimmt eine Schlüsselrolle in der Regulation physiologischer und biochemischer Prozesse von Zellen ein. Die konservierte HSP90-Familie des Menschen besteht aus vier Genen, dem zytosolischen HSP90α, der induzierbaren HSP90ß Isoform (Hickey et al., 1989), dem GRP94 im Endoplasmatischen Retikulum (Argon et al., 1999) und dem HSP75/TRAP1 in der mitochondrialen Matrix (Felts et al., 2000). Es wird angenommen, dass alle Mitglieder der Familie eine ähnliche Wirkweise haben, aber, je nach ihrer Lokalisierung in der Zelle, 5 an unterschiedliche „dient" Proteine binden. Beispielsweise ist ERBB2 ein spezifisches „dient" Protein von GRP94 (Argon et al., 1999), während der Typ1 Rezeptor des Tumornekrosefaktors (TNFR1) oder das Retino- blastom Protein (Rb) als „Clients" von TRAP1 nachgewiesen wurden (SongCollection of different proteins such as mutant p53 or the catalytic subunit of telomerase hTERT. Each of these proteins plays a key role in the regulation of physiological and biochemical processes of cells. The conserved human HSP90 family consists of four genes, the cytosolic HSP90α, the inducible HSP90β isoform (Hickey et al., 1989), GRP94 in the endoplasmic reticulum (Argon et al., 1999) and HSP75 / TRAP1 in the mitochondrial matrix (Felts et al., 2000). It is believed that all members of the family have a similar mode of action but, depending on their location in the cell, bind 5 to different "serving" proteins For example, ERBB2 is a specific "serving" protein of GRP94 (Argon et al. 1999), while the type 1 receptor of tumor necrosis factor (TNFR1) or the retinoblastoma protein (Rb) were detected as "clients" of TRAP1 (Song
10 et al., 1995; Chen et al., 1996).10 et al., 1995; Chen et al., 1996).
HSP90 ist an einer Reihe von komplexen Interaktionen mit einer grossen Zahl von „dient" Proteinen und regulatorischen Proteinen beteiligt (Smith, 2001 ). Obwohl präzise molekulare Details noch nicht geklärt sind, habenHSP90 is involved in a number of complex interactions with a large number of "serving" proteins and regulatory proteins (Smith, 2001), although precise molecular details have yet to be clarified
* 5 biochemische Experimente und Untersuchungen mit Hilfe der Röntgen- kristallographie in den letzten Jahren zunehmend Details der Chaperon- funktion von HSP90 entschlüsseln können (Prodromou et al., 1997; Stebbins et al., 1997). Danach ist HSP90 ein ATP-abhängiges molekulares Chaperon (Prodromou et al, 1997), wobei die Dimerisierung In recent years, biochemical experiments and investigations using X-ray crystallography have been able to increasingly decipher details of the chaperone function of HSP90 (Prodromou et al., 1997, Stebbins et al., 1997). Thereafter, HSP90 is an ATP-dependent molecular chaperone (Prodromou et al, 1997), with dimerization
20 wichtig für die ATP Hydrolyse ist. Die Bindung von ATP resultiert in der20 is important for ATP hydrolysis. The binding of ATP results in the
Formation einer toroidalen Dimerstruktur, bei der die beiden N-terminalen Domainen in engem Kontakt zueinander kommen und einen „switch" in der Konformation bewirken. (Prodromou and Pearl, 2000). 25Formation of a toroidal dimer structure, in which the two N-terminal domains are in close contact with each other and cause a "switch" in the conformation (Prodromou and Pearl, 2000)
Bekannte HSP90 InhibitorenKnown HSP90 inhibitors
Die erste Klasse von HSP90 Inhibitoren, die entdeckt wurde, waren Benzochinon-Ansamycine mit den Verbindungen Herbimycin A und 3(3 Geldanamycin. Ursprünglich wurde mit ihnen die Reversion des malignen Phänotyps bei Fibroblasten nachgewiesen, die durch Transformation mit dem v-Src Onkogen induziert worden war (Uehara et al., 1985).The first class of HSP90 inhibitors to be discovered were benzoquinone ansamycins with the compounds herbimycin A and 3 (3 geldanamycin), originally having been shown to reverse the malignant phenotype of fibroblasts induced by transformation with the v-Src oncogene was (Uehara et al., 1985).
Später wurde eine starke antitumorale Aktivität in vitro (Schulte et al.,1998) 35 und in vivo in Tiermodellen gezeigt (Supko et al., 1995). Immunpräzipitation und Untersuchungen an Affinitätsmatrices zeigten dann, dass der Hauptwirkmechanismus von Geldanamycin eine Bindung an HSP90 involviert (Whitesell et al., 1994; Schulte and Neckers, 1998). Darüber hinaus wurde durch röntgenkristallographische Untersuchungen gezeigt, dass Geldanamycin um die ATP-Bindestelle kompetitiert und die intrinsische ATPase Aktivität von HSP90 hemmt (Prodromou et al., 1997; Panaretou et al., 1998). Dadurch wird die Entstehung des multimeren HSP90 Komplexes, mit seiner Eigenschaft als Chaperon für „dient" Proteine zu fungieren, verhindert. Als Konsequenz werden „dient" Proteine über den Ubiquitin-Proteasom-Weg abgebaut.Later, strong antitumoral activity was demonstrated in vitro (Schulte et al., 1998) 35 and in vivo in animal models (Supko et al., 1995). Immunoprecipitation and affinity matrices studies then showed that the main mechanism of action of geldanamycin involves binding to HSP90 (Whitesell et al., 1994; Schulte and Neckers, 1998). In addition, it has been demonstrated by X-ray crystallographic studies that geldanamycin competes for the ATP binding site and inhibits the intrinsic ATPase activity of HSP90 (Prodromou et al., 1997, Panaretou et al., 1998). This prevents the formation of the multimeric HSP90 complex, which acts as a chaperone for "serving" proteins, and as a consequence "serves" proteins via the ubiquitin-proteasome pathway.
Das Geldanamycin Derivat 17- Allylamino-17-demethoxygeldanamycin (17AAG) zeigte unveränderte Eigenschaft bei der Hemmung von HSP90, der Degradation von „dient" Proteinen und antitumoraler Aktivität inThe geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17AAG) showed an unchanged property in the inhibition of HSP90, the degradation of "serving" proteins and antitumoral activity in
Zellkulturen und in Xenograft Tumormodellen (Schulte et al, 1998; Kelland et al, 1999), hatte aber eine deutlich geringere Leberzytotoxizität als Geldanamycin (Page et all 1997).17AAG wird gegenwärtig in Phasel/Il klinischen Studien geprüft.Cell cultures and in xenograft tumor models (Schulte et al, 1998, Kelland et al, 1999) had significantly lower liver cytotoxicity than geldanamycin (Page et all 1997). 17AAG is currently being tested in Phasel / Il clinical trials.
Radicicol, ein makrozyklisches Antibiotikum, zeigte ebenfalls Revision des v-Src und v-Ha-Ras induzierten malignen Phänotyps von Fibroblasten (Kwon et all 1992; Zhao et al, 1995). Radicicol degradiert eineRadicicol, a macrocyclic antibiotic, also demonstrated a revision of the v-Src and v-Ha-Ras-induced malignant phenotype of fibroblasts (Kwon et al 1992, Zhao et al, 1995). Radicicol downgrades one
Vielzahl von Signalproteinen als Konsequenz der HSP90 HemmungVariety of signaling proteins as a consequence of HSP90 inhibition
(Schulte et al., 1998). Röntgenkristallographische Untersuchungen zeigten, dass Radicicol ebenfalls an die N-terminale Domäne von HSP90 bindet und die intrinsische ATPase Aktivität hemmt (Roe et al., 1998).(Schulte et al., 1998). X-ray crystallographic studies showed that radicicol also binds to the N-terminal domain of HSP90 and inhibits intrinsic ATPase activity (Roe et al., 1998).
Antibiotika vom Coumarin Typ binden bekannterweise an die ATP Bindestelle des HSP90 Homologs DNA Gyrase in Bakterien. Das Coumarin, Novobiocin, bindet an das Carboxy-terminale Ende von HSP90, also an eine andere Stelle bei HSP90 als die Benzochinon- Ansamycine und Radicicol, welche an das N-terminale Ende von HSP90 binden.(Marcu et al., 2000b).Coumarin-type antibiotics are known to bind to the ATP binding site of the HSP90 homolog DNA gyrase in bacteria. The coumarin, novobiocin, binds to the carboxy-terminal end of HSP90, which is another site in HSP90 than the benzoquinone Ansamycins and Radicicol, which bind to the N-terminal end of HSP90 (Marcu et al., 2000b).
Die Hemmung von HSP90 durch Novobiocin resultiert in der Degradation einer großen Zahl von HSP90-abhängigen Signalproteinen (Marcu et al.,The inhibition of HSP90 by novobiocin results in the degradation of a large number of HSP90-dependent signaling proteins (Marcu et al.
2000a).2000a).
Mit PU3, einem von Purinen abgeleiteten HSP90 Inhibitor konnte die Degradation von Signalproteinen z.B. ERBB2, gezeigt werden. PU3 verursacht Zellzyklus-Arrest und Differenzierung in Brustkrebs-Zelllinien (Chiosis et al., 2001).With PU3, a purine-derived HSP90 inhibitor, the degradation of signaling proteins, e.g. ERBB2, are shown. PU3 causes cell cycle arrest and differentiation in breast cancer cell lines (Chiosis et al., 2001).
HSP90 als therapeutisches TargetHSP90 as a therapeutic target
Durch die Beteiligung von HSP90 an der Regulation einer großen Zahl von Signalwegen, die entscheidende Bedeutung am Phänotyp eines Tumors haben, und der Entdeckung, dass gewisse Naturstoffe ihren biologischen Effekt durch Hemmung der Aktivität von HSP90 ausüben, wird HSP90 gegenwärtig als neues Target für die Entwicklung eines Tumorthera- peutikum geprüft (Neckers et al., 1999).By including HSP90 in the regulation of a large number of signaling pathways that are critically important to the phenotype of a tumor, and the discovery that certain natural products exert their biological effect by inhibiting the activity of HSP90, HSP90 is currently a new target for development of a tumor therapeutic (Neckers et al., 1999).
Der Hauptmechanismus der Wirkweise von Geldanamycin, 17AAG, und Radicicol beinhaltet die Hemmung der Bindung von ATP an die ATP- Bindestelle am N-terminalen Ende des Proteins und die daraus resultierende Hemmung der intrinsischen ATPase-Aktivität von HSP90 (siehe z.B. Prodromou et al., 1997; Stebbins et al., 1997; Panaretou et al., 1998). Die Hemmung der ATPase-Aktivität von HSP90 verhindert dieThe main mechanism of action of geldanamycin, 17AAG, and radicicol involves the inhibition of binding of ATP to the ATP binding site at the N-terminal end of the protein and the consequent inhibition of the intrinsic ATPase activity of HSP90 (see, eg, Prodromou et al. 1997; Stebbins et al., 1997; Panaretou et al., 1998). The inhibition of ATPase activity of HSP90 prevents the
Rekrutierung von Co-chaperonen und favorisiert die Bildung eines HSP90Recruitment of co-chaperones and favors the formation of a HSP90
Heterokomplexes, der „dient" Proteine über den Ubiquitin-Proteasom-Weg der Degradation zuführt (siehe, z.B. Neckers et al., 1999; Kelland et al., 1999). Die Behandlung von Tumorzellen mit HSP90 Inhibitoren führt zur selektiven Degradation wichtiger Proteine mit fundamentaler Bedeutung für Prozesse wie Zellproliferation, Regulation des Zellzyklus und Apoptose. Diese Prozesse sind häufig in Tumoren dereguliert (siehe z.B. Hostein et al., 2001).Heterocomplexes that "serve" proteins via the ubiquitin-proteasome pathway of degradation (see, eg, Neckers et al., 1999; Kelland et al., 1999) .Treating tumor cells with HSP90 inhibitors leads to the selective degradation of important proteins fundamental for processes such as cell proliferation, cell cycle regulation and apoptosis. These processes are often deregulated in tumors (see, eg, Hostein et al., 2001).
Eine attraktive Rationale für die Entwicklung eines Inhibitors von HSP90 ist, dass durch gleichzeitige Degradation mehrerer Proteine, die mit dem transformierten Phänotyp im Zusammenhang stehen, eine starke tumortherapeutische Wirkung erreicht werden kann.An attractive rational for the development of an inhibitor of HSP90 is that a strong tumor therapeutic effect can be achieved by the simultaneous degradation of several proteins related to the transformed phenotype.
Im einzelnen betrifft die vorliegende Erfindung Verbindungen, die HSP90 hemmen, regulieren und/oder modulieren, Zusammensetzungen, die diese Verbindungen enthalten, sowie Verfahren zu ihrer Verwendung zur Behandlung von HSP90-bedingten Krankheiten, wie Tumorerkrankungen, virale Erkrankungen wie z.B. Hepatitis B (Waxman, 2002); Immunsuppression bei Transplantationen (Bijlmakers, 2000 and Yorgin, 2000); Entzündungsbedingte Erkrankungen (Bucci, 2000) wie Rheumatoide Arthritis, Asthma, Multiple Sklerose, Typ 1 Diabetes, Lupus Erythematodes, Psoriasis und Inflammatory Bowel Disease; ZystischeIn particular, the present invention relates to compounds which inhibit, regulate and / or modulate HSP90, compositions containing these compounds, and methods for their use in the treatment of HSP90-related diseases, such as tumor diseases, viral diseases, e.g. Hepatitis B (Waxman, 2002); Immunosuppression in transplantations (Bijlmakers, 2000 and Yorgin, 2000); Inflammatory Diseases (Bucci, 2000) such as Rheumatoid Arthritis, Asthma, Multiple Sclerosis, Type 1 Diabetes, Lupus Erythematosus, Psoriasis and Inflammatory Bowel Disease; cystic
Fibrose (Füller, 2000); Erkrankungen im Zusammenhang mit AngiogeneseFibrosis (filler, 2000); Diseases related to angiogenesis
(Hur, 2002 and Kurebayashi, 2001 ) wie z.B. diabetische Retinopathie,(Hur, 2002 and Kurebayashi, 2001), e.g. diabetic retinopathy,
Hämangiome, Endometriose und Tumorangiogenese; infektiöse Erkrankungen; Autoimmunerkrankungen; Ischämie; Förderung der Nervenregeneration (Rosen et al., WO 02/09696; Degranco et al., WO 99/51223; Gold, US 6,210,974 B1); fibrogenetische Erkrankungen, wie z.B. Sklerodermie, Polymyositis, systemischer Lupus, Leberzirrhose, Keloidbildung, interstitielle Nephritis und pulmonare Fibrose (Strehlow, WO 02/02123). Die Erfindung betrifft auch die Verwendung der erfindungsgemäßen Verbindungen zum Schutz normaler Zellen gegen Toxizität, die durch Chemotherapie verursacht ist, sowie die Verwendung bei Krankheiten, wobei Proteinfehlfaltung oder Aggregation ein Hauptkausalfaktor ist, wie z.B. Skrapie, Creutzfeldt-Jakob-Krankheit, Huntington oder AlzheimerHemangiomas, endometriosis and tumor angiogenesis; infectious diseases; Autoimmune diseases; ischemia; Promotion of nerve regeneration (Rosen et al., WO 02/09696, Degranco et al., WO 99/51223, Gold, US 6,210,974 B1); fibrogenetic diseases, e.g. Scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis (Strehlow, WO 02/02123). The invention also relates to the use of the compounds of the invention for the protection of normal cells against toxicity caused by chemotherapy, as well as for use in diseases where protein misfolding or aggregation is a major causative factor, e.g. Scrapie, Creutzfeldt-Jakob Disease, Huntington or Alzheimer's
(Sittler, Hum. Mol. Genet, 10, 1307, 2001 ; Tratzelt et al., Proc. Nat. Acad.(Sittler, Hum Mol. Genet., 10, 1307, 2001; Tratzelt et al., Proc. Nat. Acad.
Sei., 92, 2944, 1995; Winklhofer et al., J. Biol. Chem., 276, 45160, 2001). In der WO 01/72779 sind Purinverbindungen beschrieben, sowie deren Verwendung zur Behandlung von GRP94 (Homolog oder Paralog zu HSP90)-bedingten Krankheiten, wie Tumorerkrankungen, wobei das Krebsgewebe ein Sarkom oder Karzinom umfasst, ausgewählt aus der Gruppe, bestehend aus Fibrosarkom, Myxosarkom, Liposarkom, Chondrosarkom, osteogenem Sarkom, Chordom, Angiosarkom, Endo- theliosarkom, Lymphangiosarkom, Lymphangioendotheliosarkom, Synoviom, Mesotheliom, Ewing-Tumor, Leiosarkom, Rhabdomyosarkom, Kolonkarzinom, Pankreaskrebs, Brustkrebs, Ovarkrebs, Prostatakrebs,Sci., 92, 2944, 1995; Winklhofer et al., J. Biol. Chem., 276, 45160, 2001). In WO 01/72779 purine compounds are described, as well as their use for the treatment of GRP94 (homologue or paralogue to HSP90) -related diseases, such as tumors, wherein the cancerous tissue comprises a sarcoma or carcinoma selected from the group consisting of fibrosarcoma, myxosarcoma , Liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
Plattenzellkarzinom, Basalzellkarzinom, Adenokarzinom, Schweißdrüsenkarzinom, Talgdrüsenkarzinom, Papillarkarzinom, Papillaradeno- karzinomen, Cystadenokarzinomen, Knochenmarkkarzinom, broncho- genem Karzinom, Nierenzellkarzinom, Hepatom, Gallengangkarzinom, Chorionkarzinom, Seminom, embryonalem Karzinom, Wilms-Tumor, Cervix-Krebs, Hodentumor, Lungenkarzinom, kleinzelligem Lungenkarzinom, Blasenkarzinom, Epithelkarzinom, Gliom, Astrocytom,Squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonic carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,
Medulloblastom, Kraniopharyngiom, Ependymom, Pinealom, Hämangio- blastom, akustischem Neurom, Oligodendrogliom, Meningiom, Melanom,Medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangio- blastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma,
Neuroblastom, Retinoblastom, Leukämie, Lymphom, multiplem Myelom, Waldenströms Makroglobulinämie und Schwere-Kettenerkrankung.Neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia and severe chain disease.
In der WO 01/72779 ist weiterhin die Verwendung der dort genanntenIn WO 01/72779 is also the use of the mentioned therein
Verbindungen zur Behandlung von viralen Erkrankungen offenbart, wobei das virale Pathogen ausgewählt ist aus der Gruppe, bestehend aus Hepatitis Typ A, Hepatitis Typ B, Hepatitis Typ C, Influenza, Varicella, Adenovirus, Herpes-Simplex Typ I (HSV-I), Herpes Simplex Typ Il (HSV- M), Rinderpest, Rhinovirus, Echovirus, Rotavirus, respiratorischem Synzytialvirus (RSV), Papillomvirus, Papovavirus, Cytomegalievirus, Echinovirus, Arbovirus, Huntavirus, Coxsackievirus, Mumpsvirus,Compounds for the treatment of viral diseases, wherein the viral pathogen is selected from the group consisting of hepatitis type A, type B hepatitis, type C hepatitis, influenza, varicella, adenovirus, herpes simplex type I (HSV-I), herpes Simplex type II (HSV-M), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV), papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackievirus, mumps virus,
Masemvirus, Röteinvirus, Poliovirus, menschliches ImmunschwächevirusMasem virus, Röteinvirus, poliovirus, human immunodeficiency virus
Typ I (HIV-I) und menschliches Immunschwächevirus Typ Il (HIV-II). In der WO 01/72779 ist ferner die Verwendung der dort genannten Verbindungen zur GRP94-Modulation beschrieben, wobei die modulierte biologische GRP94-Aktivität eine Immunreaktion in einem Individuum, Proteintransport vom endoplasmatischen Retikulum, Genesung vom hypoxischen/anoxischen Stress, Genesung von Unterernährung, Genesung von Hitzestress, oder Kombinationen davon, hervorruft, und/oder wobei die Störung eine Art Krebs ist, eine Infektionserkrankung, eine Störung, die mit einem gestörten Proteintransport vom endo- plasmatischen Retikulum, einer Störung, die mit Ischämie / Reperfusion einhergeht, oder Kombinationen davon, wobei die die mit Ischämie / Reperfusion einhergehende Störung eine Folge von Herzstillstand, Asystole und verzögerten ventrikulären Arrythmien, Herzoperation, kardiopulmonärer Bypass-Operation, Organtransplantation, Rückenmarksverletzung, Kopftrauma, Schlaganfall, thromboembolischem Schlaganfall, hämorrhagischem Schlaganfall, cerebralem Vasospasmus, Hypotonie, Hypoglykämie, Status epilepticus, einem epileptischem Anfall, Angst,Type I (HIV-I) and Human Immunodeficiency Virus Type II (HIV-II). WO 01/72779 further describes the use of the GRP94 modulation compounds therein, wherein the modulated GRP94 biological activity comprises an immune response in an individual, protein transport from the endoplasmic reticulum, recovery from hypoxic / anoxic stress, recovery from malnutrition, recovery of heat stress, or combinations thereof, and / or wherein the disorder is a type of cancer, an infectious disease, a disorder involving disturbed protein transport from the endoplasmic reticulum, ischemia / reperfusion disorder, or combinations thereof wherein the ischemia / reperfusion-associated disorder is a consequence of cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord injury, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm , Hypotension, hypoglycemia, status epilepticus, an epileptic seizure, anxiety,
Schizophrenie, einer neurodegenerativen Störung, Alzheimer-Krankheit,Schizophrenia, a neurodegenerative disorder, Alzheimer's disease,
Chorea Huntington, amyotropher lateraler Sklerose (ALS) oder Stress beim Neugeborenen ist.Huntington's chorea, amyotrophic lateral sclerosis (ALS), or neonatal stress.
In der WO 01/72779 ist schließlich die Verwendung einer wirksamen Menge eines GRP94-Proteinmodulators zur Herstellung einesIn WO 01/72779, finally, the use of an effective amount of a GRP94 protein modulator for the preparation of a
Medikamentes bechrieben, zum Verändern einer anschließenden zellulären Reaktion auf einen ischämischen Zustand bei einer Gewebestelle in einem Individuum, durch Behandlung der Zellen an der Gewebestelle mit dem GRP94-Proteinmodulator, damit die GRP94- Aktivität in Zellen dermaßen verstärkt wird, dass eine anschließende zelluläre Reaktion auf einen ischämischen Zustand verändert wird, wobei die anschließende ischämische Bedingung vorzugsweise die Folge vonA medicament for altering a subsequent cellular response to an ischemic condition at a tissue site in an individual by treating the cells at the tissue site with the GRP94 protein modulator to enhance the GRP94 activity in cells to a subsequent cellular response an ischemic condition is changed, the subsequent ischemic condition preferably being the consequence of
Herzstillstand, Asystole und verzögerten ventrikulären Arrythmien, Herz-Cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac arrest
Operation, kardiopulmonärer Bypass-Operation, Organtransplantation,Surgery, cardiopulmonary bypass surgery, organ transplantation,
Rückenmarksverletzung, Kopftrauma, Schlaganfall, thromboembolischem Schlaganfall, hämorrhagischem Schlaganfall, cerebralem Vasospasmus, Hypotonie, Hypoglykämie, Status epilepticus, einem epileptischem Anfall, Angst, Schizophrenie, einer neurodegenerativen Störung, Alzheimer- Krankheit, Chorea Huntington, amyotropher lateraler Sklerose (ALS) oderSpinal cord injury, head trauma, stroke, thromboembolic Stroke, hemorrhagic stroke, cerebral vasospasm, hypotension, hypoglycemia, status epilepticus, epileptic seizure, anxiety, schizophrenia, neurodegenerative disorder, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), or
Stress beim Neugeborenen ist, oder wobei die Gewebestelle dasStress in the newborn is, or where the tissue site is the
Donatorgewebe für eine Transplantation ist.Donor tissue for a transplant is.
A. Kamal et al. beschreiben in Trends in Molecular Medicine, Vol. 10 No. 6 June 2004, therapeutische und diagnostische Anwendungen der HSP90 Aktivierung, u.a. zur Behandlung von Krankheiten des Zentralnervensystems und von Herzkreislauferkrankungen.A. Kamal et al. describe in Trends in Molecular Medicine, Vol. 6 June 2004, Therapeutic and Diagnostic Applications of HSP90 Activation, i.a. for the treatment of central nervous system diseases and cardiovascular diseases.
Die Identifikation von kleinen Verbindungen, die HSP90 spezifisch hemmen, regulieren und/oder modulieren, ist daher wünschenswert und ein Ziel der vorliegenden Erfindung.The identification of small compounds that specifically inhibit, regulate and / or modulate HSP90 is therefore desirable and an object of the present invention.
Es wurde gefunden, daß die erfindungsgemäßen Verbindungen und ihreIt has been found that the compounds of the invention and their
Salze bei guter Verträglichkeit sehr wertvolle pharmakologischeSalts with good compatibility very valuable pharmacological
Eigenschaften besitzen.Own properties.
Insbesondere zeigen sie inhibierende Eigenschaften des HSP90.In particular, they show inhibitory properties of HSP90.
Gegenstand der vorliegenden Erfindung sind deshalb erfindungsgemäße Verbindungen als Arzneimittel und/oder Arzneimittelwirkstoffe bei der Behandlung und/oder Prophylaxe der genannten Erkrankungen und die Verwendung von erfindungsgemäßen Verbindungen zur Herstellung eines Pharmazeutikums für die Behandlung und/oder Prophylaxe der genannten Erkrankungen wie auch ein Verfahren zur Behandlung der genannten Erkrankungen umfassend die Verabreichung eines oder mehrerer erfindungsgemäßer Verbindungen an einen Patienten mit Bedarf an einer derartigen Verabreichung. Der Wirt oder Patient kann jeglicher Säugerspezies angehören, z. B. einer Primatenspezies, besonders Menschen; Nagetieren, einschließlich Mäusen, Ratten und Hamstern; Kaninchen; Pferden, Rindern, Hunden,The present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method of treatment said diseases comprising administering one or more of the compounds of the invention to a patient in need of such administration. The host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs,
Katzen usw. Tiermodelle sind für experimentelle Untersuchungen vonCats, etc. Animal models are for experimental studies of
Interesse, wobei sie ein Modell zur Behandlung einer Krankheit desInterest, being a model for treating a disease of the
Menschen zur Verfügung stellen.To provide people.
STAND DER TECHNIKSTATE OF THE ART
In der WO 00/53169 wird die HSP90-lnhibierung mit Coumarin oder einemIn WO 00/53169, the HSP90 inhibition with coumarin or a
Coumarinderivat beschrieben.Coumarin derivative described.
In der WO 03/041643 A2 sind HSP90-inhibierende Zearalanol-Derivate offenbart.WO 03/041643 A2 discloses HSP90-inhibiting zearalanol derivatives.
HSP90-inhibierende Indazolderivate kennt man aus WO 06/010595 undHSP90-inhibiting indazole derivatives are known from WO 06/010595 and
WO 02/083648.WO 02/083648.
Weitere Literatur:Further literature:
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ZUSAMMENFASSUNG DER ERFINDUNGSUMMARY OF THE INVENTION
Die Erfindung betrifft Verbindungen der FormelThe invention relates to compounds of the formula
worin R1 H, A, (CH2)nCONH2, (CH2)nCONHA, (CH2)nCONAA\ HaI, wherein R 1 is H, A, (CH 2 ) nCONH 2 , (CH 2 ) n CONHA, (CH 2 ) n CONAA \ Hal,
(CHs)nNH2, (CH2)nNHA, (CH2JnNAA1, CN, NO2, (CH2)nAr, OAr, (CH2)nCOOH, (CH2)nCOOA, (CH2)nOH, (CH2)nOA, (CH2)nHet, COHet, C≡C-CH2SiA2A', C≡CH, C≡C-A, CH=CH-Ar1 , CH=CH-COOA, CH2CH(OH)CH2OH, O(CH2)nOH,(CHs) n NH 2 , (CH 2 ) n NHA, (CH 2 J n NAA 1 , CN, NO 2 , (CH 2 ) n Ar, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het, COHet, C≡C-CH 2 SiA 2 A ', C≡CH, C≡CA, CH = CH-Ar 1 , CH = CH-COOA, CH 2 CH (OH) CH 2 OH, O (CH 2 ) n OH,
NH(CH2)nOH, O(CH2)nOA, NH(CH2)nOA, O(CH2)nNHA, NH(CH2)nNHA, NR4R5, (CH2)nCOOA, (CH2)nCONH(CH2)2CN, NH(CH2)nAr oder CH=CH-COOH, R2 H, A, (CH2)nAr, (CH2)nHet, (CH2)nOH, (CH2)nOA,NH (CH 2 ) n OH, O (CH 2 ) n OA, NH (CH 2 ) n OA, O (CH 2 ) n NHA, NH (CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2) n CONH (CH 2) 2 CN, NH (CH 2) n Ar or CH = CH-COOH, R 2 is H, A, (CH 2) n Ar, (CH 2) n Het, ( CH 2 ) n OH, (CH 2 ) n OA,
(CH2)nNHHet, (CH2)nSA oder (CH2)nCH(OH)Ar,(CH 2 ) n NHHet, (CH 2 ) n SA or (CH 2 ) n CH (OH) Ar,
R3 A, (CHz)nAr1 (CH2)nHet, (CH2)nCN, (CH2)nNH2, (CH2)nNHA,R 3 A, (CHz) n Ar 1 (CH 2 ) n Het, (CH 2 ) n CN, (CH 2 ) n NH 2 , (CH 2 ) n NHA,
(CH2)nNAA', (CH2)nOH, (CH2)nOA oder (CH2)nNHHet, R2 und R3 zusammen mit dem N-Atom an das sie gebunden sind, auch einen unsubstituierten oder ein-, zwei- oder dreifach durch HaI, A, (CH2)nOH, (CH2)nOA und/oder =O (Carbonylsauerstoff) substituierten gesättigten, ungesättigten oder aromatischen mono- oder bicyclischen Heterocyclus, der weitere 1 bis 3 N-, O- und/oder S-Atome enthalten kann,(CH 2 ) n NAA ', (CH 2 ) n OH, (CH 2 ) n OA or (CH 2 ) n NHHet, R 2 and R 3 together with the N-atom to which they are attached, also an unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and / or = O (carbonyl oxygen) saturated, unsaturated or aromatic mono- or bicyclic heterocycle, the further 1 to 3 May contain N, O and / or S atoms,
R4, R5 jeweils unabhängig voneinander (CH2)nOH, (CH2)nOA,R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
(CH2)nNH2, (CH2)nNHA oder (CH2)nNAA\ Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI, (CH2)nOA, (CH2)nOH, (CH2)nCN, SA, SOA,(CH 2 ) n NH 2 , (CH 2 ) n NHA or (CH 2 ) n NAA \ Ar unsubstituted or one, two, three, four or five times by A, Hal, (CH 2 ) n OA, (CH 2 ) n OH, (CH 2 ) n CN, SA, SOA,
SO2A, NO2, C≡CH, (CH2)nCOOH, CHO, (CH2)nCOOA, CONH2, CONHA, CONAA1, NHCOA, CH(OH)A, (CH2)nNH2, (CH2)nNHA, (CHs)nNAA1, (CH2)nNAAr1, O(CH2)nHet1, (CH2)nHet1 , COO(CH2)nAr1 , (CH2)nNHSO2A, (CH2)nOAr1 ,SO 2 A, NO 2 , C≡CH, (CH 2 ) n COOH, CHO, (CH 2 ) n COOA, CONH 2 , CONHA, CONAA 1 , NHCOA, CH (OH) A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 3) n NAA 1 , (CH 2 ) n NAAr 1 , O (CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO (CH 2 ) n Ar 1 , ( CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 ,
O(CH2)nAr1 , SO2NH(CH2)nNH2, SO2NH2, SO2NHA, SO2NAA1, CONHAr1 , CONH(CH2)nCOOA, CONH(CH2)nCOOH, NHCO(CH2)nCOOA, NHCO(CH2)nCOOH, CONH(CH2)nNH2, CONH(CH2)nNHA, CONH(CH2)nNAA', CONH(CH2)nCN, NHCOHet, SO2Het, COHet und/oder (CH2)nCH(NH2)COOH , substituiertes Phenyl, Naphthyl, Tetrahydronaphthyl oder Biphenyl, Ar1 unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI und/oder OA substituiertes Phenyl,O (CH 2 ) n Ar 1 , SO 2 NH (CH 2 ) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 , CONHAr 1 , CONH (CH 2 ) n COOA, CONH (CH 2 ) n COOH, NHCO (CH 2 ) n COOA, NHCO (CH 2 ) n COOH, CONH (CH 2 ) n NH 2 , CONH (CH 2 ) n NHA, CONH (CH 2 ) n NAA ', CONH (CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and / or (CH 2 ) n CH (NH 2 ) COOH, substituted phenyl, naphthyl, tetrahydronaphthyl or biphenyl, Ar 1 unsubstituted or mono-, di-, tri-, tetra- or quintuply phenyl substituted by A, Hal and / or OA,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S- Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch A, (CH2)nOA, (CH2)nOH, Ar1, SH, S(O)1nA1 HaI, NO2, CN, COA, CHO, COOA, COOBenzyl, CONH2, CONHA,Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S (O) 1n A 1 Hal, NO 2 , CN, COA, CHO, COOA, COOBenzyl, CONH 2 , CONHA,
CONAA1, SO2NH2, (CH2)nNH2, (CH2)nNHA, (CH2JnNAA1, NHSO2A und/oder =0 (Carbonylsauerstoff) substituiert sein kann, Het1 einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S- Atomen, der unsubstituiert oder ein- oder zweifach durch A, OA, OH, HaI, CN und/oder =0 (Carbonylsauerstoff) substituiert sein kann,CONAA 1 , SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 J n NAA 1 , NHSO 2 A and / or = O (carbonyl oxygen) may be substituted, Het 1 is a or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono- or disubstituted by A, OA, OH, Hal, CN and / or = 0 (carbonyl oxygen) may be substituted
A, A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-10 C-Atomen, worin 1-3 nicht- benachbarte CH2-Gruppen durch O, S, SO, SO2, NH, NMe oder NEt und/oder auch 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können,A, A 'are each independently of one another unbranched or branched alkyl having 1-10 C atoms, in which 1-3 non-adjacent CH 2 groups are represented by O, S, SO, SO 2 , NH, NMe or NEt and / or 1 -5 H atoms can be replaced by F, OH and / or Cl,
Alk1, cyclisches Alkyl mit 3-8 C-Atomen oder Cycloalkylalkylen, worin 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können, Alk1 Alkenyl oder Alkinyl mit 2-6 C-Atomen, m O, 1 oder 2, n O, 1 , 2, 3 oder 4, bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate undAlk 1 , cyclic alkyl having 3-8 C atoms or cycloalkylalkylene, in which 1-5 H atoms may be replaced by F, OH and / or Cl, Alk 1 alkenyl or alkynyl having 2-6 C atoms, m O, 1 or 2, n is O, 1, 2, 3 or 4, and their pharmaceutically usable derivatives, salts, solvates and
Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen. Gegenstand der Erfindung sind die Verbindungen der Formel I und ihre Salze sowie ein Verfahren zur Herstellung von Verbindungen der Formel I sowie ihrer pharmazeutisch verwendbaren Derivate, Solvate, Salze und Stereoisomere, dadurch gekennzeichnet, daß manStereoisomers, including mixtures thereof in all ratios. The invention relates to the compounds of formula I and their salts and to a process for the preparation of compounds of formula I and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, characterized in that
a) eine Verbindung der Formel Ila) a compound of formula II
worin R1 die in Anspruch 1 angegebene Bedeutung hat, und L F, Cl, Br, I oder eine freie oder eine reaktionsfähig abgewandelte OH-Gruppe bedeutet, wherein R 1 has the meaning given in claim 1, and LF, Cl, Br, I or a free or a reactively modified OH group,
mit einer Verbindung der Formel IMwith a compound of formula IM
NHR2R3 IIINHR 2 R 3 III
worin R2 und R3 die in Anspruch 1 angegebenen Bedeutungen haben,wherein R 2 and R 3 have the meanings given in claim 1,
umsetzt,implements,
oderor
b) eine Verbindung der Formel IV 1 2 3 worin R , R und R die in Anspruch 1 angegebenen Bedeutungen haben,b) a compound of formula IV Wherein R, R and R have the meanings given in claim 1,
mit einem 1 ,3-Bis(trialkylsilyl)carbodiimid umsetzt,with a 1, 3-bis (trialkylsilyl) carbodiimide,
oderor
c) in einer Verbindung der Formel I einen Rest R1 in einen anderen Rest R1 umwandelt, indem manc) in a compound of the formula I converts a radical R 1 into another radical R 1 by
i) eine Nitrogruppe zu einer Aminogruppe reduziert, ü) eine Estergruppe zu einer Carboxygruppe hydrolysiert, iii) eine Aldehydgruppe durch reduktive Aminierung in ein alkyliertesi) reducing a nitro group to an amino group, ü) hydrolyzing an ester group to a carboxy group, iii) preparing an aldehyde group by reductive amination into an alkylated one
Amin umwandelt, iv) eine Carboxygruppe in eine Sulfonamidocarbonylgruppe umwandelt, v) ein Säurechlorid in ein Amid überführt, vi) ein Halogenatom gegen einen Aryl- oder Alkylrest austauscht, vii) eine Doppelbindung hydriert, viii) einen Ether spaltet, ix) ein Halogenatom durch einen Arylrest ersetzt (Suzuki-Kopplung), x) ein Halogenatom durch eine Alkylamino-, Arylamino-, Alkoxy- oder eine Aryloxygruppe ersetzt, und/oder eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.V) converting a halogen atom to an aryl or alkyl radical, vii) hydrogenating a double bond, viii) cleaving an ether, ix) a halogen atom replacing an aryl radical (Suzuki coupling), x) replacing a halogen atom with an alkylamino, arylamino, alkoxy or an aryloxy group, and / or converting a base or acid of the formula I into one of its salts.
Gegenstand der Erfindung sind auch die Stereoisomeren (E, Z-Isomeren) sowie die Hydrate und Solvate dieser Verbindungen. Unter Solvate der Verbindungen werden Anlagerungen von inerten Lösungsmittelmolekülen an die Verbindungen verstanden, die sich aufgrund ihrer gegenseitigen Anziehungskraft ausbilden. Solvate sind z.B. Mono- oder Dihydrate oder Alkoholate.The invention also relates to the stereoisomers (E, Z isomers) and the hydrates and solvates of these compounds. Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.
Unter pharmazeutisch verwendbaren Derivaten versteht man z.B. diePharmaceutically usable derivatives are understood, for example, as the
Salze der erfindungsgemäßen Verbindungen als auch sogenannteSalts of the compounds of the invention as well as so-called
Prodrug-Verbindungen.Prodrug compounds.
Unter Prodrug-Derivaten versteht man mit z. B. Alkyl- oder Acylgruppen, Zuckern oder Oligopeptiden abgewandelte Verbindungen der Formel I, die im Organismus rasch zu den wirksamen erfindungsgemäßenUnder prodrug derivatives is understood with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which in the body rapidly to the effective invention
Verbindungen gespalten werden.Connections are split.
Hierzu gehören auch bioabbaubare Polymerderivate der erfindungs- gemäßen Verbindungen, wie dies z. B. in Int. J. Pharm. 115, 61-67 (1995) beschrieben ist.These include biodegradable polymer derivatives of the inventive compounds, as z. In Int. J. Pharm. 115, 61-67 (1995).
Der Ausdruck "wirksame Menge" bedeutet die Menge eines Arzneimittels oder eines pharmazeutischen Wirkstoffes, die eine biologische oder medizinische Antwort in einem Gewebe, System, Tier oder Menschen hervorruft, die z.B. von einem Forscher oder Mediziner gesucht oder erstrebt wird.The term "effective amount" means the amount of a drug or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.
Darüberhinaus bedeutet der Ausdruck "therapeutisch wirksame Menge" eine Menge, die, verglichen zu einem entsprechenden Subjekt, das diese Menge nicht erhalten hat, folgendes zur Folge hat: verbesserte Heilbehandlung, Heilung, Prävention oder Beseitigung einer Krankheit, eines Krankheitsbildes, eines Krankheitszustandes, eines Leidens, einer Störung oder von Nebenwirkungen oder auch dieMoreover, the term "therapeutically effective amount" means an amount that, as compared to a corresponding subject who has not received that amount, results in: improved treatment, cure, prevention or elimination of a disease, a clinical picture, a disease state, a disease, a disorder or side effects or the
Verminderung des Fortschreitens einer Krankheit, eines Leidens oder einer Störung.Reduction of the progression of a disease, a disease or a disorder.
Die Bezeichnung "therapeutisch wirksame Menge" umfaßt auch die Mengen, die wirkungsvoll sind, die normale physiologische Funktion zu erhöhen.The term "therapeutically effective amount" also includes the amounts effective to increase normal physiological function.
Gegenstand der Erfindung sind auch Mischungen der erfindungsgemäßen Verbindungen der Formel I, z.B. Gemische zweier Diastereomerer z.B. im Verhältnis 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 oder 1 :1000. Besonders bevorzugt handelt es sich dabei um Mischungen stereoisomerer Verbindungen.The invention also provides mixtures of the compounds of the formula I according to the invention, e.g. Mixtures of two diastereomers, e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
Für alle Reste, die mehrfach auftreten, gilt, daß deren Bedeutungen unabhängig voneinander sind.For all residues which occur several times, their meanings are independent of each other.
Vor- und nachstehend haben die Reste bzw. Parameter R1, R2 und R3 die bei der Formel I angegebenen Bedeutungen, falls nicht ausdrücklich etwas anderes angegeben ist.Above and below, the radicals or parameters R 1 , R 2 and R 3 have the meanings given for the formula I, unless expressly stated otherwise.
Carbamoyl bedeutet Aminocarbonyl.Carbamoyl means aminocarbonyl.
BOC oder Boc bedeutet tert.-Butyloxycarbonyl.Boc or Boc means tert-butyloxycarbonyl.
A bzw. A' bedeutet vorzugsweise Alkyl, ist unverzweigt (linear) oder verzweigt, und hat 1 , 2, 3, 4, 5, 6, 7, 8, 9 oder 10 C-Atome. A bzw. A' bedeutet besonders bevorzugt Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek. -Butyl oder tert.-Butyl, ferner auch Pentyl, 1-, 2- oder 3- Methylbutyl, 1 ,1- , 1 ,2- oder 2,2-Dimethylpropyl, 1-Ethylpropyl, Hexyl, 1- , 2- , 3- oder 4-Methylpentyl, 1,1- , 1 ,2- , 1 ,3- , 2,2- , 2,3- oder 3,3-A or A 'is preferably alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms. A or A 'is particularly preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl or tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-
Dimethylbutyl, 1- oder 2-Ethylbutyl, 1-Ethyl-1-methylpropyl, 1-Ethyl-2- methylpropyl, 1 ,1 ,2- oder 1 ,2,2-Trimethylpropyl. A bzw. A' bedeutet ganz besonders bevorzugt Alkyl mit 1 , 2, 3, 4, 5 oder 6 C-Atomen, vorzugsweise Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek - Butyl, tert.-Butyl, Pentyl, Hexyl, Trifluormethyl, Pentafluorethyl oder 1,1 ,1-Dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 or 1,2,2-trimethylpropyl. A or A 'very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, Trifluoromethyl, pentafluoroethyl or 1,1, 1-
Trifluorethyl.Trifluoroethyl.
A, A' bedeuten auch jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-10 C-Atomen, worin 1-3 nicht-benachbarte CH2- Gruppen durch O, S, SO, SO2, NH, NMe1 oder NEt ersetzt sein können, wie z.B. 2-Methoxy-ethyl oder 3-Methylamino-propyl. A bzw. A' bedeutet auch cyclisches Alkyl (Cycloalkyl). Cycloalkyl bedeutet vorzugsweise Cyclopropyl, Cyclobutyl, Cylopentyl, Cyclohexyl oder Cycloheptyl. Cyclisches Alkyl bedeutet weiterhin vorzugsweise Cyclopropylmethyl, Cyclopentylmethyl oder Cyclohexylmethyl. Cycloalkylalkylen bedeutet z.B. Cyclopropylmethylen oder Cyclohexylmethy len .A, A 'also each independently represent unbranched or branched alkyl having 1-10 C atoms, in which 1-3 non-adjacent CH 2 groups have been replaced by O, S, SO, SO 2 , NH, NMe 1 or NEt can, such as 2-methoxy-ethyl or 3-methylamino-propyl. A or A 'also means cyclic alkyl (cycloalkyl). Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cyclic alkyl furthermore preferably denotes cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl. Cycloalkylalkylene means, for example, cyclopropylmethylene or cyclohexylmethy len.
A bzw. A' bedeutet auch Alk1. Alk1 bedeutet Alkenyl mit 2-6 C-Atomen, wie z.B. Vinyl oder Propenyl. Alk1 bedeutet auch Alkinyl wie z.B. Ethinyl.A or A 'also means Alk 1 . Alk 1 is alkenyl having 2-6 C atoms, such as vinyl or propenyl. Alk 1 also means alkynyl such as ethynyl.
n bedeutet vorzugsweise 0, 1 oder 2.n is preferably 0, 1 or 2.
R2 und R3 bedeuten vorzugsweise, zusammen mit dem N-Atom an das sie gebunden sind, auch unsubstituiertes oder ein-, zwei- oder dreifach durch HaI, A, (CH2)nOH, (CH2)nOA und/oder =O (Carbonylsauerstoff) substituiertes 1 ,3-Dihydro-isoindolyl, Azepanyl, Pyrrolidinyl, Piperazinyl, Piperidinyl oder Morpholinyl, ganz besonders bevorzugt ist 1 ,3-Dihydro- isoindol-2-yl.R 2 and R 3 are preferably, together with the N atom to which they are attached, also unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and / or = O (carbonyl oxygen) substituted 1, 3-dihydro-isoindolyl, azepanyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl, very particular preference is 1, 3-dihydro-isoindol-2-yl.
R2 bedeutet vorzugsweise H, Methyl, Ethyl, 2-Hydroxyethyl, 2- Methoxyethyl, 2-(Pyridin-2-ylamino)-ethyl oder Benzyl.R 2 is preferably H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2- (pyridin-2-ylamino) ethyl or benzyl.
^ R3 bedeutet vorzugsweise Methyl, Ethyl, Propyl, Butyl, Isopropyl, Phenyl, Benzyl, Furyl-2-ylmethyl, HC≡C-CH2-, 2-Methoxy-ethyl, 3-Trifluormethyl- 46R 3 is preferably methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl, furyl-2-ylmethyl, HC≡C-CH 2 -, 2-methoxy-ethyl, 3-trifluoromethyl- 46
- 26 -- 26 -
benzyl, Pyridin-2- oder 3-ylmethyl, 2-, 3- oder 4-Fluor-benzyl, 2-, 3- oder 4- Methoxy-benzyl, 2-, 3- oder 4-Methylbenzyl, 3-Chlor-6-methoxy-benzyl, N,N-Dimethylamino-carbonylmethyl, 4-([1 ,2,4]Triazol-1-ylmethyl)-benzyl, 2- oder 3-(Pyridin-3-yl)-benzyl, 3-(2-Morpholin-4-yl-ethoxy)-benzyl, 4-(Triazol-benzyl, pyridin-2 or 3-ylmethyl, 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-methylbenzyl, 3-chloro-6 -methoxybenzyl, N, N-dimethylamino-carbonylmethyl, 4 - ([1, 2,4] triazol-1-ylmethyl) benzyl, 2- or 3- (pyridin-3-yl) benzyl, 3- ( 2-morpholin-4-yl-ethoxy) -benzyl, 4- (triazole)
1-yl)-benzyl, 3-(Morpholin-4-yl)-benzyl, 3-(Pyrimidin-5-yl)-benzyl, 3-1-yl) benzyl, 3- (morpholin-4-yl) benzyl, 3- (pyrimidin-5-yl) benzyl, 3
(Morpholin-4-ylmethyl)-benzyl, Cyclopropylmethyl, 2-Cyanethyl, 2- Dimethylamino-ethyl, Cyclohexyl, 3- oder 4-(Methylsulfonylamino)-benzyl, 4-(Methylsulfonylaminomethyl)-benzyl, Benzo[1 ,4]dioxan-6-ylmethyl, Morpholin-4-yl, 2-Hydroxyethyl, 2-Methoxyethyl, 1 ,3,5-Trimethyl-1 H- pyrazol-4-ylmethyl,(Morpholin-4-ylmethyl) benzyl, cyclopropylmethyl, 2-cyanoethyl, 2-dimethylamino-ethyl, cyclohexyl, 3- or 4- (methylsulfonylamino) -benzyl, 4- (methylsulfonylaminomethyl) -benzyl, benzo [1,4] dioxane 6-ylmethyl, morpholin-4-yl, 2-hydroxyethyl, 2-methoxyethyl, 1, 3,5-trimethyl-1H-pyrazol-4-ylmethyl,
2-Methylsulfanil-ethyl, 2-Hydroxy-2-phenyl-ethyl, 2-(N-Ethyl-N-methyl- amino)-ethyl, 2-Diethylamino-ethyl, 1-Methyl-1H-pyrazol-3-yl, Chinolin-5- oder 8-yl, 2-Methylsulfanil-phenyl, Biphenyl-2-yl, 5,6,7, 8-Tetrahydro- naphthalin-1-yl, 2-(1 H-Benzimidazol-2-yl)-phenyl, 3,4,5-Trimethoxy-phenyl, 2-Ethinylphenyl oder 1-Methyl-5-trifluormethyl-1H-indazol-3-yl.2-methylsulfanilethyl, 2-hydroxy-2-phenylethyl, 2- (N-ethyl-N-methylamino) ethyl, 2-diethylaminoethyl, 1-methyl-1H-pyrazol-3-yl, Quinoline-5- or 8-yl, 2-methylsulfanil-phenyl, biphenyl-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 2- (1H-benzimidazol-2-yl) - phenyl, 3,4,5-trimethoxyphenyl, 2-ethynylphenyl or 1-methyl-5-trifluoromethyl-1H-indazol-3-yl.
Ar bedeutet z.B. Phenyl, o-, m- oder p-Tolyl, o-, m- oder p-Ethylphenyl, o-, m- oder p-Propylphenyl, o-, m- oder p-lsopropylphenyl, o-, m- oder p-tert-Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert
Butylphenyl, o-, m- oder p-Hydroxyphenyl, o-, m- oder p-Nitrophenyl, o-, m- oder p-Aminophenyl, o-, m- oder p-(N-Methylamino)-phenyl, o-, m- oder p- (N-Methylaminocarbonyl)-phenyl, o-, m- oder p-Acetamidophenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Ethoxy- carbonylphenyl, o-, m- oder p-(N,N-Dimethylamino)-phenyl, o-, m- oder p- (N,N-Dimethylaminocarbonyl)-phenyl, o-, m- oder p-(N-Ethylamino)-phenyl, o-, m- oder p-(N,N-Diethylamino)-phenyl, o-, m- oder p-Fluorphenyl, o-, m- oder p-Bromphenyl, o-, m- oder p- Chlorphenyl, o-, m- oder p-(Methyl- sulfonamido)-phenyl, o-, m- oder p-(Methylsulfonyl)-phenyl, o-, m- oder p- Cyanphenyl, o-, m- oder p-Acetylphenyl, o-, m- oder p-Aminosulfonyl- phenyl, o-, m- oder p-Carboxyphenyl, o-, m- oder p-Carboxymethyl-phenyl, o-, m- oder p-Carboxymethoxy-phenyl, weiter bevorzugt 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Difluorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5- Dichlorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dibromphenyl, 2,4- oder 2,5-Dinitrophenyl, 2,5- oder 3,4-Dimethoxyphenyl, 3-Nitro-4-chlorphenyl, 3- Amino-4-chlor-, 2-Amino-3-chlor-, 2-Amino-4-chlor-, 2-Amino-5-chlor- oder 2-Amino-6-chlorphenyl, 2-Nitro-4-N,N-dimethylamino- oder 3-Nitro-4-N,N- dimethylaminophenyl, 2,3-Diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- oderButylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o- , m- or p- (N-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N, N-dimethylaminocarbonyl) -phenyl, o-, m- or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m - or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p- (methylsulfonyl) -phenyl, o-, m- or p-cyanophenyl, o-, m - or p-acetylphenyl, o-, m- or p-aminosulfonyl-phenyl, o-, m- or p-carboxyphenyl, o-, m- or p-carboxymethyl-phenyl, o-, m- or p-carboxymethoxy- phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro , 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or
3,4,5-Trichlorphenyl, 2,4,6-Trimethoxyphenyl, 2-Hydroxy-3,5-dichlorphenyl, p-lodphenyl, 3,6-Dichlor-4-aminophenyl, 4-Fluor-3-chlorphenyl, 2-Fluor-4- bromphenyl, 2,5-Difluor-4-bromphenyl, 3-Brom-6-methoxyphenyl, 3-Chlor- 6-methoxyphenyl, 3-Chlor-4-acetamidophenyl, 3-Fluor-4-methoxyphenyl, 3-Amino-6-methylphenyl, 3-Chlor-4-acetamidophenyl oder 2,5-Dimethyl-4- chlorphenyl.3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2- Fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3 Amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
Het bedeutet, ungeachtetet weiterer Substitutionen, z.B. 2- oder 3-Furyl, 2- oder 3-Thienyl, 1-, 2- oder 3-Pyrrolyl, 1-, 2, 4- oder 5-lmidazolyl, 1-, 3-, A- oder 5-Pyrazolyl, 2-, 4- oder 5-Oxazolyl, 3-, 4- oder 5-lsoxazolyl, 2-, A- oder 5-Thiazolyl, 3-, 4- oder 5-lsothiazolyl, 2-, 3- oder 4-Pyridyl, 2-, 4-, 5- oder 6- Pyrimidinyl, weiterhin bevorzugt 1,2,3-Triazol-1-, -4- oder -5-yl, 1 ,2,4-Het, irrespective of further substitutions, e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, A- or 5-pyrazolyl, 2 -, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, A- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 , 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazole-1, -4- or -5-yl, 1, 2,4-
Triazol-1-, -3- oder 5-yl, 1- oder 5-Tetrazolyl, 1 ,2,3-Oxadiazol-4- oder -5-yl,Triazole-1, 3, or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or 5-yl,
1 ,2,4-Oxadiazol-3- oder -5-yl, 1 ,3,4-Thiadiazol-2- oder -5-yl, 1 ,2,4-1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1, 2,4-
Thiadiazol-3- oder -5-yl, 1 ,2,3-Thiadiazol-4- oder -5-yl, 3- oder A- Pyridazinyl, Pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- oder 7-lndolyl, 4- oder 5- Isoindolyl, 1-, 2-, 4- oder 5-Benzimidazolyl, 1-, 2-, 3-, A-, 5-, 6- oder 7- Indazolyl, 1-, 3-, A-, 5-, 6- oder 7-Benzopyrazolyl, 2-, A-, 5-, 6- oder 7- Benzoxazolyl, 3-, A-, 5-, 6- oder 7- Benzisoxazolyl, 2-, 4-, 5-, 6- oder 7- Benzothiazolyl, 2-, A-, 5-, 6- oder 7-Benzisothiazolyl, A-, 5-, 6- oder 7-Benz- 2,1 ,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- oder 8-Chinolyl, 1-, 3-, A-, 5-, 6-, 7- oder 8-lsochinolyl, 3-, A-, 5-, 6-, 7- oder 8-Cinnolinyl, 2-, 4-, 5-, 6-, 7- oder 8-Chinazolinyl, 5- oder 6-Chinoxalinyl, 2-, 3-, 5-, 6-, 7- oder 8-2H-Benzo- [1 ,4]oxazinyl, weiter bevorzugt 1 ,3-Benzodioxol-5-yl, 1 ,4-Benzodioxan-6-yl, 2,1 ,3-Benzothiadiazol-4- oder -5-yl oder 2,1 ,3-Benzoxadiazol-5-yl.Thiadiazol-3 or -5-yl, 1, 2,3-thiadiazol-4 or -5-yl, 3- or A-pyridazinyl, pyrazinyl, 1, 2, 3, 4, 5, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, A-, 5-, 6- or 7-indazolyl, 1 -, 3-, A-, 5-, 6- or 7-benzopyrazolyl, 2-, A-, 5-, 6- or 7- benzoxazolyl, 3-, A-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7- benzothiazolyl, 2-, A-, 5-, 6- or 7-benzisothiazolyl, A-, 5-, 6- or 7-Benz-2,1, 3 oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, A-, 5-, 6-, 7- or 8-isoquinolyl, 3-, A, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5- , 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazole 4- or 5-yl or 2,1,3-benzoxadiazol-5-yl.
Die heterocyclischen Reste können auch teilweise oder vollständig hydriert sein. Het kann also z. B. auch bedeuten 2,3-Dihydro-2-, -3-, -4- oder -5-furyl, 2,5-Dihydro-2-, -3-, -4- oder 5-furyl, Tetrahydro-2- oder -3-furyl, 1 ,3-Dioxo- lan-4-yl, Tetrahydro-2- oder -3-thienyl, 2,3-Dihydro-1-, -2-, -3-, -4- oder -5- pyrrolyl, 2,5-Dihydro-1-, -2-, -3-, -4- oder -5-pyrrolyl, 1-, 2- oder 3-Pyrroli- 5 dinyl, Tetrahydro-1-, -2- oder -4-imidazolyl, 2,3-Dihydro-1-, -2-, -3-, -4- oderThe heterocyclic radicals may also be partially or completely hydrogenated. Het can so z. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-, -3-, -4- or -5- pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrroli- 5-dinyl, tetrahydro-1-, - 2- or 4-imidazolyl, 2,3-dihydro-1-, 2-, -3-, -4- or
-5-pyrazolyl, Tetrahydro-1-, -3- oder -4-pyrazolyl, 1 ,4-Dihydro-1-, -2-, -3- oder -4-pyridyl, 1,2,3,4-Tetrahydro-1-, -2-, -3-, -4-, -5- oder -6-pyridyl, 1-, 2-, 3- oder 4-Piperidinyl, 2-, 3- oder 4-Morpholinyl, Tetrahydro-2-, -3- oder -5-pyrazolyl, tetrahydro-1-, 3- or 4-pyrazolyl, 1,4-dihydro-1-, 2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro 1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro- 2-, 3- or -
10 4-pyranyl, 1 ,4-Dioxanyl, 1 ,3-Dioxan-2-, -4- oder -5-yl, Hexahydro-1-, -3- oder -4-pyridazinyl, Hexahydro-1-, -2-, -4- oder -5-pyrimidinyl, 1-, 2- oder 3- Piperazinyl, 1 ,2,3,4-Tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- oder -8-chinolyl, 1 ,2,3,4-Tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- oder -8-isochinolyl, 2-, 3-, 5-,10 4-pyranyl, 1,4-dioxanyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2 -, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3,4-tetrahydro-1 -, - 2 -, - 3, -4, -5-, -6-, -7- or 8-isoquinolyl, 2-, 3-, 5-,
A g 6-, 7- oder 8- 3,4-Dihydro-2H-benzo[1 ,4]oxazinyl, weiter bevorzugt 2,3- Methylendioxyphenyl, 3,4-Methylendioxyphenyl, 2,3-Ethylendioxyphenyl, 3,4-Ethylendioxyphenyl, 3,4-(Difluormethylendioxy)phenyl, 2,3-Dihydro- benzofuran-5- oder 6-yl, 2,3-(2-Oxo-methylendioxy)-phenyl oder auch 3,4-A g is 6-, 7- or 8-3,4-dihydro-2H-benzo [1,4] oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4- Ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxomethylenedioxy) -phenyl or else 3,4-
Dihydro-2H-1 ,5-benzodioxepin-6- oder -7-yl, ferner bevorzugt 2,3-Dihydro-Dihydro-2H-1, 5-benzodioxepin-6 or -7-yl, furthermore preferably 2,3-dihydroxy
20 benzofuranyl oder 2,3-Dihydro-2-oxo-furanyl.20 benzofuranyl or 2,3-dihydro-2-oxofuranyl.
Het bedeutet vorzugsweise unsubstituiertes oder ein-, zwei- oder dreifach durch A, (CH2)nOA, (CH2)nOH, Ar1, SH, S(O)mA, HaI, NO2, CN, COA, CHO,Het is preferably unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S (O) m A, Hal, NO 2 , CN, COA, CHO,
25 COOA, COOBenzyl, CONH2, CONHA, CONAA1, SO2NH2, (CH2)nNH2, (CH2)nNHA, (CH^nNAA1, NHSO2A und/oder =0 (Carbonylsauerstoff) substituiertes Pyridyl, Pyrimidinyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Benzothiazolyl,25 COOA, COOBenzyl, CONH 2 , CONHA, CONAA 1 , SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH) n NAA 1 , NHSO 2 A and / or = O (carbonyl oxygen ) substituted pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl,
30 Benzo[1 ,4]dioxanyl, Chinolyl, Isochinolyl, Chinazolinyl, Benzimidazolyl, Indazolyl, Indolyl, 1 ,3-Dihydro-isoindolyl, Benzofuranyl, Dihydro- benzofuranyl, Benzo[1 ,3]dioxolyl, Piperazinyl, Pyrazinyl, Pyridazinyl, Morpholinyl, Azepanyl, Pyrrolidinyl oder Piperidinyl. 30 Benzo [1,4] dioxanyl, quinolyl, isoquinolyl, quinazolinyl, benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzofuranyl, benzo [1,3] dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl , Azepanyl, pyrrolidinyl or piperidinyl.
O CO C
Het1 bedeutet, ungeachtetet weiterer Substitutionen, z.B. 2- oder 3-Furyl, 2- oder 3-Thienyl, 1-, 2- oder 3-Pyrrolyl, 1-, 2, 4- oder 5-lmidazolyl, 1-, 3-, A- oder 5-Pyrazolyl, 2-, A- oder 5-Oxazolyl, 3-, 4- oder 5-lsoxazolyl, 2-, A- oder 5-Thiazolyl, 3-, 4- oder 5-lsothiazolyl, 2-, 3- oder 4-Pyridyl, 2-, 4-, 5- oder 6-Pyrimidinyl, weiterhin bevorzugt 1 ,2,3-Triazol-1-, -A- oder -5-yl,Het 1 , notwithstanding further substitutions, for example 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3- . A- or 5-pyrazolyl, 2-, A- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, A- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2,3-triazole-1, -A- or -5-yl,
1 ,2,4-Triazol-1-, -3- oder 5-yl, 1- oder 5-Tetrazolyl, 1 ,2,3-Oxadiazol-4- oder1, 2,4-triazole-1, -3 or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazole-4 or
-5-yl, 1 ,2,4-Oxadiazol-3- oder -5-yl, 1,3,4-Thiadiazol-2- oder -5-yl, 1 ,2,4- Thiadiazol-3- oder -5-yl, 1 ,2,3-Thiadiazol-4- oder -5-yl, 3- oder A- Pyridazinyl, Pyrazinyl, 1-, 2-, 3-, A-, 5-, 6- oder 7-lndolyl, 4- oder 5- Isoindolyl, 1-, 2-, A- oder 5-Benzimidazolyl, 1-, 2-, 3-, A-, 5-, 6- oder 7- Indazolyl, 1-, 3-, A-, 5-, 6- oder 7-Benzopyrazolyl, 2-, A-, 5-, 6- oder 7- Benzoxazolyl, 3-, A-, 5-, 6- oder 7- Benzisoxazolyl, 2-, 4-, 5-, 6- oder 7- Benzothiazolyl, 2-, A-, 5-, 6- oder 7-Benzisothiazolyl, A-, 5-, 6- oder 7-Benz- 2,1 ,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- oder 8-Chinolyl, 1-, 3-, A-, 5-, 6-, 7- oder 8-lsochinolyl, 3-, A-, 5-, 6-, 7- oder 8-Cinnolinyl, 2-, 4-, 5-, 6-, 7- oder 8-Chinazolinyl, 5- oder 6-Chinoxalinyl, 2-, 3-, 5-, 6-, 7- oder 8-2H-Benzo- [1 ,4]oxazinyl, weiter bevorzugt 1 ,3-Benzodioxol-5-yl, 1 ,4-Benzodioxan-6-yl, 2,1 ,3-Benzothiadiazol-4- oder -5-yl oder 2,1 ,3-Benzoxadiazol-5-yl.-5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1,3,4-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazole-3 or -5 -yl, 1, 2,3-thiadiazol-4 or -5-yl, 3- or A-pyridazinyl, pyrazinyl, 1-, 2-, 3-, A-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, A- or 5-benzimidazolyl, 1-, 2-, 3-, A-, 5-, 6- or 7- indazolyl, 1-, 3-, A- , 5-, 6- or 7-benzopyrazolyl, 2-, A-, 5-, 6- or 7- benzoxazolyl, 3-, A-, 5-, 6- or 7- Benzisoxazolyl, 2-, 4-, 5 -, 6- or 7- benzothiazolyl, 2-, A-, 5-, 6- or 7-Benzisothiazolyl, A-, 5-, 6- or 7-Benz-2,1,3-oxadiazolyl, 2-, 3 -, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, A-, 5-, 6-, 7- or 8-isoquinolyl, 3-, A-, 5-, 6 -, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-Benzo- [1,4] oxazinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4 or 5-yl or 2,1,3-benzoxadiazol-5-yl.
Die heterocyclischen Reste können auch teilweise oder vollständig hydriert sein.The heterocyclic radicals may also be partially or completely hydrogenated.
Het kann also z. B. auch bedeuten 2,3-Dihydro-2-, -3-, -A- oder -5-furyl, 2,5-Dihydro-2-, -3-, -A- oder 5-furyl, Tetrahydro-2- oder -3-furyl, 1,3-Dioxo- lan-4-yl, Tetrahydro-2- oder -3-thienyl, 2,3-Dihydro-1-, -2-, -3-, -4- oder -5- pyrrolyl, 2,5-Dihydro-1-, -2-, -3-, -A- oder -5-pyrrolyl, 1-, 2- oder 3-Pyrroli- dinyl, Tetrahydro-1-, -2- oder -4-imidazolyl, 2,3-Dihydro-1-, -2-, -3-, -A- oder -5-pyrazolyl, Tetrahydro-1-, -3- oder -4-pyrazolyl, 1 ,4-Dihydro-1-, -2-, -3- oder -4-pyridyl, 1 ,2,3,4-Tetrahydro-1-, -2-, -3-, -A-, -5- oder -6-pyridyl, 1-, 2-, 3- oder 4-Piperidinyl, 2-, 3- oder 4-Morpholinyl, Tetra hydro-2-, -3- oder - 4-pyranyl, 1 ,4-Dioxanyl, 1 ,3-Dioxan-2-, -A- oder -5-yl, Hexahydro-1-, -3- oder -4-pyridazinyl, Hexahydro-1-, -2-, -A- oder -5-pyrimidinyl, 1-, 2- oder 3- Piperazinyl, 1 ,2,3,4-Tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- oder -8-chinolyl,Het can so z. B. also mean 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or 5-furyl, tetrahydro-2 - or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-, -3-, -4- or -5- pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2 - or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -A- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4 Dihydro-1-, 2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -A-, -5- or -6 pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2, 3 or 4-pyranyl, 1, 4-dioxanyl, 1, 3 Dioxane-2-, -A- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -A- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, 2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl,
1 ,2,3,4-Tetrahydro-1-,-2-,-3-, -A-, -5-, -6-, -7- oder -8-isochinolyl, 2-, 3-, 5-,1,2,3,4-tetrahydro-1, -2, 3, A, 5, 6, 7 or 8 isoquinolyl, 2, 3, 5 .
6-, 7- oder 8- 3,4-Dihydro-2H-benzo[1,4]oxazinyl, weiter bevorzugt 2,3-6-, 7- or 8-3,4-dihydro-2H-benzo [1,4] oxazinyl, more preferably 2,3-
Methylendioxyphenyl, 3,4-Methylendioxyphenyl, 2,3-Ethylendioxyphenyl, 3,4-Ethylendioxyphenyl, 3,4-(Difluormethylendioxy)phenyl, 2,3-Dihydro- benzofuran-5- oder 6-yl, 2,3-(2-Oxo-methylendioxy)-phenyl oder auch 3,4- Dihydro-2H-1 ,5-benzodioxepin-6- oder -7-yl, ferner bevorzugt 2,3-Dihydro- benzofuranyl oder 2,3-Dihydro-2-oxo-furanyl.Methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxomethylenedioxy) -phenyl or also 3,4-dihydro 2H-1, 5-benzodioxepin-6 or -7-yl, further preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.
Het1 bedeutet besonders bevorzugt unsubstituiertes oder ein-, zwei- oder dreifach durch A, OA, OH1 HaI, CN und/oder =O (Carbonylsauerstoff) substituiertes Pyridyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Triazolyl, Benzimidazolyl, Morpholinyl, Pyrimidinyl, Piperidinyl, Pyrrolidinyl oder Piperazinyl.Het 1 particularly preferably denotes pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, benzimidazolyl, morpholinyl, pyrimidinyl which is unsubstituted or mono-, di- or trisubstituted by A, OA, OH 1 Hal, CN and / or OO (carbonyl oxygen) , Piperidinyl, pyrrolidinyl or piperazinyl.
Die Verbindungen der Formel I können ein oder mehrere chirale Zentren besitzen und daher in verschiedenen stereoisomeren Formen vorkommen. Die Formel I umschließt alle diese Formen.The compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms. Formula I encompasses all these forms.
Dementsprechend sind Gegenstand der Erfindung insbesondere diejenigen Verbindungen der Formel I1 in denen mindestens einer der genanntenAccordingly, the invention are in particular those compounds of formula I 1 where at least one of said
Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat.Rests has one of the preferred meanings given above.
Einige bevorzugte Gruppen von Verbindungen können durch die folgendenSome preferred groups of compounds may be through the following
Teilformeln Ia bis Ii ausgedrückt werden, die der Formel I entsprechen und worin die nicht näher bezeichneten Reste die bei der Formel I angegebenePartial formulas Ia to Ii are expressed which correspond to the formula I and wherein the unspecified radicals corresponding to those given in formula I.
Bedeutung haben, worin jedochMeaning, in which, however
in Ia Het unsubstituiertes oder ein-, zwei- oder dreifach durch A,in Ia Het unsubstituted or one, two or three times by A,
(CH2)nOA, (CH2)nOH, Ar1, SH, S(O)nA HaI, NO2, CN, COA, CHO, COOA, COOBenzyl, CONH2, CONHA, CONAA1, SO2NH2, (CH2)nNH2, (CH2)nNHA, (CHz)nNAA1,(CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S (O) n A Hal, NO 2 , CN, COA, CHO, COOA, COOBenzyl, CONH 2 , CONHA, CONAA 1 , SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CHz) n NAA 1 ,
NHSO2A und/oder =0 (Carbonylsauerstoff) substituiertes Pyridyl, Pyrimidinyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Oxazolyl,NHSO 2 A and / or = 0 (carbonyl oxygen) substituted pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,
Isoxazolyl, Thiazolyl, Benzothiazolyl, Benzo[1 ,4]- dioxanyl, Chinolyl, Isochinolyl, Chinazolinyl,Isoxazolyl, thiazolyl, benzothiazolyl, benzo [1,4] dioxanyl, quinolyl, isoquinolyl, quinazolinyl,
Benzimidazolyl, Indazolyl, Indolyl, 1 ,3-Dihydro- isoindolyl, Benzofuranyl, Dihydro-benzofuranyl, Benzo[1 ,3]dioxolyl, Piperazinyl, Pyrazinyl, Pyridazinyl, Morpholinyl, Azepanyl, Pyrrolidinyl oder Piperidinyl, bedeutet; 5 in Ib Het1 unsubstituiertes oder ein-, zwei- oder dreifach durch A,Benzimidazolyl, indazolyl, indolyl, 1, 3-dihydro- isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzo [1,3] dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, pyrrolidinyl or piperidinyl; 5 in Ib Het 1 unsubstituted or one, two or three times by A,
OA, OH, HaI, CN und/oder =O (Carbonylsauerstoff) substituiertes Pyridyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, 10 Benzimidazolyl, Triazolyl, Morpholinyl, Pyrimidinyl,OA, OH, Hal, CN and / or OO (carbonyl oxygen) substituted pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, benzimidazolyl, triazolyl, morpholinyl, pyrimidinyl,
Piperidinyl, Pyrrolidinyl oder Piperazinyl, bedeutet;Piperidinyl, pyrrolidinyl or piperazinyl;
15 in Ic A1 A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-6 C-Atomen, worin 1-2 CH2- Gruppen durch O, NH und/oder NMe und/oder auch 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können, oder 15 in Ic A 1 A 'are each independently of one another unbranched or branched alkyl having 1-6 C atoms, in which 1-2 CH 2 - groups by O, NH and / or NMe and / or also 1-5 H-atoms by F , OH and / or Cl can be replaced, or
20 cyclisches Alkyl mit 3-8 C-Atomen, worin 1-3 H-Atome durch OH ersetzt sein können, bedeuten;20 cyclic alkyl having 3-8 C atoms, wherein 1-3 H atoms may be replaced by OH, mean;
25 in Id n 0, 1 oder 2 bedeutet;25 in Id n means 0, 1 or 2;
in Ie R2 und R3 zusammen mit dem N-Atom an das sie gebundenin Ie R 2 and R 3 together with the N atom to which they are attached
„n sind, auch unsubstituiertes oder ein-, zwei- oder dreifach durch HaI, A, (CH2)nOH, (CH2)nOA und/oder =O (Carbonylsauerstoff) substituiertes 1 ,3-Dihydro-isoindolyl, Pyrrolidinyl, Azepanyl," N are also unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and / or = O (carbonyl oxygen) substituted, 1, 3-dihydro-isoindolyl, pyrrolidinyl , Azepanyl,
Piperazinyl, Piperidinyl oder Morpholinyl,Piperazinyl, piperidinyl or morpholinyl,
35 . . 4 bedeuten; 8 00484635. , 4 mean; 8 004846
- 32 -- 32 -
in If R2 H, Methyl, Ethyl, 2-Hydroxyethyl, 2-Methoxyethyl, 2-in If R 2 is H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2
(Pyridin-2-ylamino)-ethyl oder Benzyl, bedeuten;(Pyridin-2-ylamino) ethyl or benzyl;
in Ig R3 Methyl, Ethyl, Propyl, Butyl, Isopropyl, Phenyl, Benzyl,in Ig R 3 methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl,
Furyl-2-ylmethyl, HC≡C-CH2-, 2-Methoxy-ethyl, 3- Trifluormethyl-benzyl, Pyridin-2- oder 3-ylmethyl, 2-, 3- oder 4-Fluor-benzyl, 2-, 3- oder 4-Methoxy-benzyl, 2-, 3-0 oder 4-Methylbenzyl, 3-Chlor-6-methoxy-benzyl, N1N-Furyl-2-ylmethyl, HC≡C-CH 2 -, 2-methoxy-ethyl, 3-trifluoromethyl-benzyl, pyridin-2 or 3-ylmethyl, 2-, 3- or 4-fluoro-benzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3-0 or 4-methylbenzyl, 3-chloro-6-methoxybenzyl, N 1 N-
Dimethylamino-carbonylmethyl, 4-([1 ,2,4]Triazol-1- ylmethyl)-benzyl, 2- oder 3-(Pyridin-3-yl)-benzyl, 3-(2- Morpholin-4-yl-ethoxy)-benzyl, 4-(Triazol-1-yl)-benzyl, 3-5 (Morpholin-4-yl)-benzyl, 3-(Pyrimidin-5-yl)-benzyl, 3-Dimethylamino-carbonylmethyl, 4 - ([1, 2,4] triazol-1-ylmethyl) -benzyl, 2- or 3- (pyridin-3-yl) -benzyl, 3- (2-morpholin-4-yl-ethoxy ) -benzyl, 4- (triazol-1-yl) benzyl, 3- 5 (morpholin-4-yl) -benzyl, 3- (pyrimidin-5-yl) benzyl, 3-
(Morpholin-4-ylmethyl)-benzyl, Cyclopropylmethyl, 2- Cyanethyl, 2-Dimethylamino-ethyl, Cyclohexyl, 3- oder 4-(Methylsulfonylamino)-benzyl, 4-(Methylsulfonylamino- methyl)-benzyl, Benzo[1 ,4]dioxan-6-ylmethyl, Morpholin-Ω(Morpholin-4-ylmethyl) benzyl, cyclopropylmethyl, 2-cyanoethyl, 2-dimethylamino-ethyl, cyclohexyl, 3- or 4- (methylsulfonylamino) -benzyl, 4- (methylsulfonylamino-methyl) -benzyl, benzo [1, 4 ] dioxan-6-ylmethyl, morpholine-Ω
4-yl, 2-Hydroxyethyl, 2-Methoxyethyl, 1 ,3,5-Trimethyl-4-yl, 2-hydroxyethyl, 2-methoxyethyl, 1, 3,5-trimethyl
1H-pyrazol-4-ylmethyl, 2-Methylsulfanil-ethyl, 2- Hydroxy-2-phenyl-ethyl, 2-(N-Ethyl-N-methyl-amino)- ethyl, 2-Diethylamino-ethyl, 1-Methyl-1H-pyrazol-3-yl,5 Chinolin-5- oder 8-yl, 2-Methylsulfanil-phenyl, Biphenyl-1H-pyrazol-4-ylmethyl, 2-methylsulfanil-ethyl, 2-hydroxy-2-phenyl-ethyl, 2- (N-ethyl-N-methyl-amino) -ethyl, 2-diethylamino-ethyl, 1-methyl- 1H-pyrazol-3-yl, 5-quinolin-5 or 8-yl, 2-methylsulfanil-phenyl, biphenyl
2-yl, 5,6,7,8-Tetrahydro-naphthalin-i-yl, 2-(1 H- Benzimidazol-2-yl)-phenyl, 3,4,5-Trimethoxy-phenyl, 2- Ethinylphenyl oder 1-Methyl-5-trifluormethyl-1H-indazol-0 3-y- bedeutet;2-yl, 5,6,7,8-tetrahydronaphthalen-i-yl, 2- (1H-benzimidazol-2-yl) -phenyl, 3,4,5-trimethoxyphenyl, 2-ethynylphenyl or 1 Methyl 5-trifluoromethyl-1H-indazole-0 3 -y-;
in Ih R1 H, A, (CH2)nCONH2, (CH2)nCONHA, (CH2)nCONAA',in Ih R 1 is H, A, (CH 2 ) n CONH 2 , (CH 2 ) n CONHA, (CH 2 ) n CONAA ',
HaI, (CH2)nNH2, (CH2)nNHA, (CH2)nNAA', CN, NO2,5 . (CH2)nAr, OAr, (CH2)nCOOH, (CH2)nCOOA, (CH2)nOH,Hal, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA ', CN, NO 2 , 5 . (CH 2 ) n Ar, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA, (CH 2 ) n OH,
(CHz)nOA, (CH2)nHet, COHet, C=C-CH2SiA2A1, C≡CH, C≡C-A, CH=CH-Ar1, CH=CH-COOA, CH2CH(OH)CH2OH, O(CH2)nOH, NH(CH2)nOH, O(CH2)nOA, NH(CH2)nOA, O(CH2)nNHA, NH(CH2)nNHA, NR4R5, (CH2)nCOOA, (CH2)nCONH(CH2)2CN, NH(CH2)nAr oder CH=CH-COOH1 (CHz) n OA, (CH 2 ) n Het, COHet, C = C-CH 2 SiA 2 A 1 , C≡CH, C≡CA, CH = CH-Ar 1 , CH = CH-COOA, CH 2 CH (OH) CH 2 OH, O (CH 2 ) n OH, NH (CH 2 ) n OH, O (CH 2 ) n OA , NH (CH 2 ) n OA, O (CH 2 ) n NHA, NH (CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH (CH 2 ) 2 CN, NH (CH 2 ) n Ar or CH = CH-COOH 1
R2 H, A, (CH2)nAr, (CH2)nHet, (CH2)nOH, (CH2)nOA, (CH2)nNHHet, (CH2)nSA oder (CH2)nCH(OH)Ar, R3 A, (CH2)nAr, (CH2)nHet, (CH2)nCN, (CH2)nNH2, (CH2)nNHA, (CH2)RNAA1, (CH2)nOH, (CH2)nOA oderR 2 is H, A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NHHet, (CH 2 ) n SA or (CH 2 ) n CH (OH) Ar, R 3 A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n CN, (CH 2 ) n NH 2 , (CH 2 ) n NHA, ( CH 2 ) RNAA 1 , (CH 2 ) n OH, (CH 2 ) n OA or
(CH2)nNHHet,(CH 2 ) n NHHet,
R2 und R3 zusammen mit dem N-Atom an das sie gebunden sind, auch unsubstituiertes oder ein-, zwei- oder dreifach durch HaI, A, (CH2)nOH, (CH2)nOA und/oder =OR 2 and R 3 together with the N-atom to which they are attached, also unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and / or = O
(Carbonylsauerstoff) substituiertes 1,3-Dihydro- isoindolyl, Azepanyl, Pyrrolidinyl, Piperazinyl, Piperidinyl oder Morpholinyl, R4, R5 jeweils unabhängig voneinander (CH2)nOH, (CH2)nOA, (CH2)nNH2, (CH2)nNHA oder (CHz)nNAA1,(Carbonyl oxygen) substituted 1,3-dihydroisoindolyl, azepanyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl, R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NH 2 , (CH 2 ) n NHA or (CHz) n NAA 1 ,
Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI, (CH2)nOA, (CH2)nOH, (CH2)nCN, SA, SOA, SO2A, NO2, C≡CH, (CH2)nCOOH, CHO, (CH2)nCOOA, CONH2, CONHA, CONAA1, NHCOA,Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, (CH 2 ) n OA, (CH 2 ) n OH, (CH 2 ) n CN, SA, SOA, SO 2 A, NO 2 , C≡CH, (CH 2 ) n COOH, CHO, (CH 2 ) n COOA, CONH 2 , CONHA, CONAA 1 , NHCOA,
CH(OH)A, (CH2)nNH2, (CH2)nNHA, (CHz)nNAA1, (CH2)nNAAr1, O(CH2)nHet1, (CH2)nHet1, COO(CH2)nAr1, (CH2)nNHSO2A, (CH2)nOAr1, O(CH2)nAr1, SO2NH(CH2)nNH2, SO2NH2, SO2NHA, SO2NAA1,CH (OH) A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CHz) n NAA 1 , (CH 2 ) n NAAr 1 , O (CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO (CH 2 ) n Ar 1 , (CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 , O (CH 2 ) n Ar 1 , SO 2 NH (CH 2 ) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 ,
CONHAr1, CONH(CH2)nCOOA, CONH(CH2)nCOOH, NHCO(CH2)nCOOA, NHCO(CH2)nCOOH, CONH(CH2)nNH2, CONH(CH2)nNHA, CONH(CH2)ONAA1, CONH(CH2)nCN, NHCOHet, SO2Het, COHet und/oder (CH2)nCH(NH2)COOH substituiertes Phenyl, Naphthyl, Tetrahydronaphthyl oder Biphenyl, Ar1 unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI und/oder OA substituiertes Phenyl, Het unsubstituiertes oder ein-, zwei- oder dreifach durch A, (CH2)nOA, (CH2)nOH, Ar1, SH, S(O)nA HaI, NO2, CN,CONHAr 1 , CONH (CH 2 ) n COOA, CONH (CH 2 ) n COOH, NHCO (CH 2 ) n COOA, NHCO (CH 2 ) n COOH, CONH (CH 2 ) n NH 2 , CONH (CH 2 ) n NHA, CONH (CH 2 ) O, NAA 1 , CONH (CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and / or (CH 2 ) n CH (NH 2 ) COOH substituted phenyl, naphthyl, tetrahydronaphthyl or biphenyl, Ar 1 is unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl, substituted by A, Hal and / or OA, H is unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S (O) n A Hal, NO 2 , CN,
COA, CHO, COOA, COOBenzyl, CONH2, CONHA, CONAA1, SO2NH2, (CH2)nNH2, (CH2)nNHA, (CH2)nNAA\ NHSO2A und/oder =O (Carbonylsauerstoff) substituiertes Pyridyl, Pyrimidinyl, Furyl, Thienyl,COA, CHO, COOA, COOBenzyl, CONH 2 , CONHA, CONAA 1 , SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA \ NHSO 2 A and / or O (carbonyl oxygen) substituted pyridyl, pyrimidinyl, furyl, thienyl,
Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Benzothiazolyl, Benzo[1 ,4]- dioxanyl, Chinolyl, Isochinolyl, Chinazolinyl, Benzimidazolyl, Indazolyl, Indolyl, 1 ,3-Dihydro- isoindolyl, Benzofuranyl, Dihydro-benzofuranyl, Benzo[1 ,3]dioxolyl, Piperazinyl, Pyrazinyl, Pyridazinyl, Morpholinyl, Azepanyl, Pyrrolidinyl oder Piperidinyl,Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, benzo [1,4] dioxanyl, quinolyl, isoquinolyl, quinazolinyl, benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzofuranyl , Benzo [1,3] dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, pyrrolidinyl or piperidinyl,
Het1 unsubstituiertes oder ein-, zwei- oder dreifach durch A,Het 1 is unsubstituted or mono-, di- or trisubstituted by A,
OA, OH, HaI, CN und/oder =0 (Carbonylsauerstoff) substituiertes Pyridyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Benzimidazolyl, Triazolyl, Morpholinyl, Pyrimidinyl, Piperidinyl, Pyrrolidinyl oder Piperazinyl, A, A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-6 C-Atomen, worin 1-2 CH2- Gruppen durch O, NH und/oder NMe und/oder auch 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können, oder cyclisches Alkyl mit 3-8 C-Atomen, worin 1-3 H-Atome durch OH ersetzt sein können, m O, 1 oder 2, n O, 1 oder 2, . . . bedeuten; R1 H, A1 (CH2)nCONH2, (CH2)nCONHA, (CHs)nCONAA1,OA, OH, Hal, CN and / or = O (carbonyl oxygen) substituted pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, benzimidazolyl, triazolyl, morpholinyl, pyrimidinyl, piperidinyl, pyrrolidinyl or piperazinyl, A, A 'are each independently unbranched or branched Alkyl having 1-6 C atoms, in which 1-2 CH 2 groups may be replaced by O, NH and / or NMe and / or also 1-5 H atoms by F, OH and / or Cl, or the cyclic one Alkyl having 3-8 C atoms, wherein 1-3 H atoms may be replaced by OH, m is O, 1 or 2, n is O, 1 or 2 ,. , , mean; R 1 H, A 1 (CH 2 ) n CONH 2 , (CH 2 ) n CONHA, (CHs) n CONAA 1 ,
HaI, (CH2)nNH2, (CH2)nNHA, (CH2)nNAA\ CN, NO2, (CH2)nAr, OAr, (CH2)nCOOH, (CH2)nCOOA, (CH2)nOH, (CH2)nOA, (CH2)nHet, COHet, C≡C-CH2SiA2A', C≡CH, C=C-A, CH=CH-Ar1, CH=CH-COOA1 Hal, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA \ CN, NO 2 , (CH 2 ) n Ar, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA , (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het, COHet, C≡C-CH 2 SiA 2 A ', C≡CH, C = CA, CH = CH-Ar 1 , CH = CH-COOA 1
CH2CH(OH)CH2OH, O(CH2)nOH, NH(CH2)nOH, O(CH2)nOA, NH(CH2)nOA, O(CH2)nNHA, NH(CH2)nNHA, NR4R5, (CH2)nCOOA, (CH2)nCONH(CH2)2CN, NH(CH2)nAr oder CH=CH-COOH,CH 2 CH (OH) CH 2 OH, O (CH 2 ) n OH, NH (CH 2 ) n OH, O (CH 2 ) n OA, NH (CH 2 ) n OA, O (CH 2 ) n NHA, NH (CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH (CH 2 ) 2 CN, NH (CH 2 ) n Ar or CH = CH-COOH,
R2 H, Methyl, Ethyl, 2-Hydroxyethyl, 2-Methoxyethyl, 2-R 2 is H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2
(Pyridin-2-ylamino)-ethyl oder Benzyl, R3 Methyl, Ethyl, Propyl, Butyl, Isopropyl, Phenyl, Benzyl, Furyl-2-ylmethyl, HC≡C-CH2-, 2-Methoxy-ethyl, 3-(Pyridin-2-ylamino) -ethyl or benzyl, R 3 is methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl, furyl-2-ylmethyl, HC≡C-CH 2 -, 2-methoxy-ethyl, 3
Trifluormethyl-benzyl, Pyridin-2- oder 3-ylmethyl, 2-, 3- oder 4-Fluor-benzyl, 2-, 3- oder 4-Methoxy-benzyl, 2-, 3- oder 4-Methylbenzyl, 3-Chlor-6-methoxy-benzyl, N1N-Trifluoromethylbenzyl, pyridin-2 or 3-ylmethyl, 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-methylbenzyl, 3-chloro 6-methoxybenzyl, N 1 N-
Dimethylamino-carbonylmethyl, 4-([1 ,2,4]Triazol-1- ylmethyl)-benzyl, 2- oder 3-(Pyridin-3-yl)-benzyl, 3-(2-Dimethylamino-carbonylmethyl, 4 - ([1, 2,4] triazol-1-ylmethyl) benzyl, 2- or 3- (pyridin-3-yl) benzyl, 3- (2-
Morpholin-4-yl-ethoxy)-benzyl, 4-(Triazol-1-yl)-benzyl, 3- (Morpholin-4-yl)-benzyl, 3-(Pyrimidin-5-yl)-benzyl, 3- (Morpholin-4-ylmethyl)-benzyl, Cyclopropylmethyl, 2- Cyanethyl, 2-Dimethylamino-ethyl, Cyclohexyl, 3- oderMorpholin-4-yl-ethoxy) -benzyl, 4- (triazol-1-yl) -benzyl, 3- (morpholin-4-yl) -benzyl, 3- (pyrimidin-5-yl) -benzyl, 3- ( Morpholin-4-ylmethyl) benzyl, cyclopropylmethyl, 2-cyanoethyl, 2-dimethylamino-ethyl, cyclohexyl, 3-or
4-(Methylsulfonylamino)-benzyl, 4-(Methylsulfonylamino- methyl)-benzyl, Benzo[1 ,4]dioxan-6-ylmethyl, Morpholin- 4-yl, 2-Hydroxyethyl, 2-Methoxyethyl, 1 ,3,5-Trimethyl- 1 H-pyrazol-4-ylmethyl, 2-Methylsulfanil-ethyl, 2-4- (methylsulfonylamino) -benzyl, 4- (methylsulfonylamino-methyl) -benzyl, benzo [1,4] dioxan-6-ylmethyl, morpholin-4-yl, 2-hydroxyethyl, 2-methoxyethyl, 1, 3,5- Trimethyl-1H-pyrazol-4-ylmethyl, 2-methylsulfanil-ethyl, 2-
Hydroxy-2-phenyl-ethyl, 2-(N-Ethyl-N-methyl-amino)- ethyl, 2-Diethylamino-ethyl, 1-Methyl-1H-pyrazol-3-yl, Chinolin-5- oder 8-yl, 2-Methylsulfanil-phenyl, Biphenyl-Hydroxy-2-phenyl-ethyl, 2- (N-ethyl-N-methyl-amino) -ethyl, 2-diethylamino-ethyl, 1-methyl-1H-pyrazol-3-yl, quinoline-5 or 8-yl , 2-methylsulfanilphenyl, biphenyl
2-yl, 5,6,7, 8-Tetrahydro-naphthalin-1-yl, 2-(1 H-2-yl, 5,6,7, 8-tetrahydro-naphthalen-1-yl, 2- (1H-
Benzimidazol-2-yl)-phenyl, 3,4,5-Trimethoxy-phenyl, 2- Ethinylphenyl oder 1-Methyl-5-trifluormethyl-1 H-indazol-Benzimidazol-2-yl) -phenyl, 3,4,5-trimethoxyphenyl, 2- Ethynylphenyl or 1-methyl-5-trifluoromethyl-1H-indazole
3-yl, R2 und R3 zusammen mit dem N-Atom an das sie gebunden sind, auch unsubstituiertes oder ein-, zwei- oder 5 dreifach durch HaI, A, (CHz)nOH1 (CH2)nOA und/oder =O3-yl, R 2 and R 3 to which they are together with the N-atom attached may also form unsubstituted or mono-, di- or 5 trisubstituted by Hal, A, (CHz) n OH 1 (CH 2) n OA and / or = O
(Carbonylsauerstoff) substituiertes 1 ,3-Dihydro- isoindolyl, Azepanyl, Pyrrolidinyl, Piperazinyl, Piperidinyl oder Morpholinyl, 10 R4, R5 jeweils unabhängig voneinander (CH2)nOH, (CH2)nOA,(Carbonyl oxygen) substituted 1,3-dihydroisoindolyl, azepanyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl, 10 R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
(CH2)nNH2, (CH2)nNHA oder (CH2)nNAA', Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI, (CH2)nOA, (CH2)nOH, (CH2)nCN, 15 SA, SOA, SO2A, NO2, C≡CH, (CH2)nCOOH, CHO,(CH 2 ) n NH 2 , (CH 2 ) n NHA or (CH 2 ) n NAA ', Ar unsubstituted or one, two, three, four or five times by A, Hal, (CH 2 ) n OA , (CH 2 ) n OH, (CH 2 ) n CN, 15 SA, SOA, SO 2 A, NO 2 , C≡CH, (CH 2 ) n COOH, CHO,
(CH2)nCOOA, CONH2, CONHA, CONAA1, NHCOA,(CH 2 ) n COOA, CONH 2 , CONHA, CONAA 1 , NHCOA,
CH(OH)A, (CH2)nNH2, (CH2)nNHA, (CHz)nNAA1,CH (OH) A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CHz) n NAA 1 ,
(CH2)nNAAr1, O(CH2)nHet\ (CH2)nHet1, COO(CH2)nAr1 ,(CH 2 ) n NAAr 1 , O (CH 2 ) n Het \ (CH 2 ) n Het 1 , COO (CH 2 ) n Ar 1 ,
(CH2)nNHSO2A, (CH2)nOAr1, O(CH2)nAr1, on(CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 , O (CH 2 ) n Ar 1 , on
SO2NH(CHz)nNH2, SO2NH2, SO2NHA, SO2NAA1,SO 2 NH (CHz) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 ,
CONHAr1, CONH(CHz)nCOOA, CONH(CH2)nCOOH,CONHAr 1 , CONH (CHz) n COOA, CONH (CH 2 ) n COOH,
NHCO(CH2)nCOOA, NHCO(CH2)nCOOH,NHCO (CH 2 ) n COOA, NHCO (CH 2 ) n COOH,
CONH(CH2)nNH2, CONH(CH2)nNHA, CONH(CH2)nNAA\ 25 CONH(CH2)nCN, NHCOHet, SO2Het, COHet und/oderCONH (CH 2 ) n NH 2 , CONH (CH 2 ) n NHA, CONH (CH 2 ) n NAA 25 CONH (CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and / or
(CH2)nCH(NH2)COOH substituiertes Phenyl, Naphthyl,(CH 2 ) n CH (NH 2 ) COOH substituted phenyl, naphthyl,
Tetrahydronaphthyl oder Biphenyl, Ar1 unsubstituiertes oder ein-, zwei-, drei-, vier- oder ^0 fünffach durch A, HaI und/oder OA substituiertesTetrahydronaphthyl or biphenyl, Ar 1 unsubstituted or mono-, di-, tri-, tetra- or ^ 0 five-fold substituted by A, Hal and / or OA
Phenyl, Het unsubstituiertes oder ein-, zwei- oder dreifach durchPhenyl, Het unsubstituted or mono-, di- or trisubstituted
HaI, Phenyl, A, (CH2)nOH, (CH2)nOA, COOH, COOA,Hal, phenyl, A, (CH 2 ) n OH, (CH 2 ) n OA, COOH, COOA,
COOBenzyl, CN, COA, CHO, (CHz)nNH2, (CH2)nNHA,COOBenzyl, CN, COA, CHO, (CHz) n NH 2 , (CH 2 ) n NHA,
3535
(CH2)nNAA' und/oder =0 (Carbonylsauerstoff) substituiertes Pyridyl, Pyrimidinyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Benzothiazolyl, Benzo[1 ,4]- dioxanyl, Chinolyl, Isochinolyl, Chinazolinyl,(CH 2 ) n NAA 'and / or = 0 (carbonyl oxygen) substituted pyridyl, pyrimidinyl, furyl, thienyl, Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, benzo [1,4] dioxanyl, quinolyl, isoquinolyl, quinazolinyl,
Benzimidazolyl, Indazolyl, Indolyl, 1 ,3-Dihydro- isoindolyl, Benzofuranyl, Dihydro-benzofuranyl,Benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzofuranyl,
Benzo[1 ,3]dioxolyl, Piperazinyl, Pyrazinyl, Pyridazinyl, Morpholinyl, Azepanyl, Pyrrolidinyl oder Piperidinyl, Het1 unsubstituiertes oder einfach durch =O (Carbonylsauerstoff) substituiertes Morpholinyl,Benzo [1, 3] dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, pyrrolidinyl or piperidinyl, Het 1 unsubstituted or simply by = O (carbonyl oxygen) substituted morpholinyl,
Piperidinyl oder Pyrrolidinyl,Piperidinyl or pyrrolidinyl,
A, A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-6 C-Atomen, worin 1-2 CH2- Gruppen durch O, NH und/oder NMe und/oder auch 1-5A, A 'are each independently of one another unbranched or branched alkyl having 1-6 C atoms, in which 1-2 CH 2 - groups by O, NH and / or NMe and / or also 1-5
H-Atome durch F, OH und/oder Cl ersetzt sein können, oder cyclisches Alkyl mit 3-8 C-Atomen, worin 1-3 H-Atome durch OH ersetzt sein können, m 0, 1 oder 2, n 0, 1 oder 2, bedeuten; sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Salze und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.H atoms may be replaced by F, OH and / or Cl, or cyclic alkyl having 3-8 C atoms, in which 1-3 H atoms may be replaced by OH, m is 0, 1 or 2, n is 0, 1 or 2, mean; and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including mixtures thereof in all ratios.
Die erfindungsgemäßen Verbindungen und auch die Ausgangsstoffe zu ihrer Herstellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wieThe compounds according to the invention and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as
Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten VariantenHouben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart) are described, under reaction conditions, which are known and suitable for the said reactions. One can also of known per se, not mentioned here variants
Gebrauch machen. 8 004846Make use. 8 004846
- 38 -- 38 -
Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den erfindungsgemäßen Verbindungen umsetzt.The starting materials can, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of the invention.
Die Ausgangsverbindungen sind in der Regel bekannt. Sind sie neu, so können sie aber nach an sich bekannten Methoden hergestellt werden.The starting compounds are generally known. If they are new, they can be produced by methods known per se.
Verbindungen der Formel I können vorzugsweise erhalten werden, indem man eine Verbindung der Formel Il mit einer Verbindung der Formel IM umsetzt.Compounds of the formula I can preferably be obtained by reacting a compound of the formula II with a compound of the formula III.
In den Verbindungen der Formel Il bedeutet L vorzugsweise F, Cl, Br, I oder eine freie oder eine reaktionsfähig abgewandelte OH-Gruppe wie z.B. ein aktivierter Ester, ein Imidazolid oder Alkylsulfonyloxy mit 1-6 C-Atomen (bevorzugt Methylsulfonyloxy oder Trifluormethylsulfonyloxy) oder Aryl- sulfonyloxy mit 6-10 C-Atomen (bevorzugt Phenyl- oder p-Tolylsulfonyl- oxy). In den Verbindungen der Formel Il bedeutet L vorzugsweise Cl.In the compounds of formula II, L is preferably F, Cl, Br, I or a free or a reactively modified OH group, e.g. an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyl-oxy). In the compounds of the formula II, L is preferably Cl.
Die Umsetzung erfolgt in der Regel in einem inerten Lösungsmittel, inThe reaction is usually carried out in an inert solvent, in
Gegenwart eines säurebindenden Mittels vorzugsweise eines Alkali- oderPresence of an acid-binding agent, preferably an alkali or
Erdalkalimetall-hydroxids, -carbonats oder -bicarbonats oder eines anderen Salzes einer schwachen Säure der Alkali- oder Erdalkalimetalle, vorzugsweise des Kaliums, Natriums, Calciums oder Cäsiums. Auch der Zusatz einer organischen Base wie Triethylamin, Dimethylanilin, Pyridin oder Chinolin kann günstig sein.Alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline may be beneficial.
Wird eine Verbindung der Formel II, worin L OH bedeutet, mit einem Amin umgesetzt, so gibt man vorzugsweise ein Kupplungsreagenz vor und/oder während der Umsetzung zu, z.B. Ethyl-2-ethoxy-1 ,2-dihydrochinolin-1- carboxylat oder Propanphosphonsäure-cycloanhydrid.When a compound of formula II wherein L is OH is reacted with an amine, it is preferable to add a coupling reagent before and / or during the reaction, e.g. Ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate or propanephosphonic acid cycloanhydride.
Die Umsetzung erfolgt nach Methoden, die dem Fachmann bekannt sind.The reaction is carried out by methods known to the person skilled in the art.
Zunächst erfolgt Reaktion in einem geeigneten Lösungsmittel. AIs Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder XyIoI; chlorierte Kohlenwasserstoffe wie Trichlorethylen, 1 ,2-Dichlorethan, Tetrachlorkohlenstoff, Chlorform oderFirst, reaction takes place in a suitable solvent. Examples of suitable solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or
Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Tetrahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykol- monomethyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylenglykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon;0 Amide wie Acetamid, Dimethylacetamid oder Dimethylformamid (DMF); Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Schwefelkohlenstoff; Carbonsäuren wie Ameisensäure oder Essigsäure; Nitroverbindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat oder c Gemische der genannten Lösungsmittel.dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; 0 amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or c mixtures of the solvents mentioned.
Als Lösungsmittel besonders bevorzugt ist Acetonitril oder DMF.Particularly preferred solvents are acetonitrile or DMF.
Die Reaktionszeit liegt je nach den angewendeten Bedingungen zwischen einigen Minuten und 14 Tagen, die Reaktionstemperatur zwischen etwa 0°0 und 150°, normalerweise zwischen 15° und 120°, besonders bevorzugt zwischen 50° und 1000C.The reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about 0 ° 0 and 150 °, usually between 15 ° and 120 °, more preferably between 50 ° and 100 0 C.
Es ist ferner möglich, eine Verbindung der Formel I in eine andere Ver-5 bindung der Formel I umzuwandeln, indem man einen Rest R1 in einen anderen Rest R1 umwandelt, z.B. indem man Nitrogruppen, beispielsweise durch Hydrierung an Raney-Nickel oder Pd-Kohle in einem inerten Lösungsmittel wie Methanol oder Ethanol, zu Aminogruppen reduziert0 und/oder eine Estergruppe in eine Carboxygruppe umwandelt und/oder eine Aldehydgruppe durch reduktive Aminierung in ein alkyliertes Amin umwandelt und/oderIt is also possible to convert a compound of the formula I into another compound of the formula I by converting a radical R 1 into another radical R 1 , for example by reacting nitro groups, for example by hydrogenation on Raney nickel or Pd -Cool in an inert solvent such as methanol or ethanol, reduced to amino groups 0 and / or converts an ester group into a carboxy group and / or converts an aldehyde group by reductive amination in an alkylated amine and / or
Carboxygruppen durch Umsetzung mit Alkoholen verestert und/oder5Esterified carboxy groups by reaction with alcohols and / or5
Säurechloride durch Umsetzung mit einem Amin in ein Säureamid überführt. Femer kann man freie Amino- und /oder Hydroxygruppen in üblicher Weise mit einem Säurechlorid oder -anhydrid acylieren oder mit einem unsubstituierten oder substituierten Alkylhalogenid alkylieren, zweckmäßig in einem inerten Lösungsmittel wie Dichlormethan oder THF und /oder in Gegenwart einer Base wie Triethylamin oder Pyridin bei Temperaturen zwischen -60 und +30°.Acid chlorides are converted by reaction with an amine in an acid amide. Furthermore, free amino and / or hydroxy groups may be acylated in the usual manner with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, conveniently in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine Temperatures between -60 and + 30 °.
Etherspaltungen erfolgen nach Methoden, die dem Fachmann bekannt sind. Die Reaktion erfolgt in einem geeigneten Lösungsmittel, wie oben angegeben, vorzugsweise durch Zugabe von Bortribromid. Die Reaktion erfolgt besonders bevorzugt in Dichlormethan bei einer Reaktionstemperatur zwischen etwa -30° und 50°, normalerweise zwischen -20° und 20°, insbesondere zwischen etwa -15° und etwa 0°.Ether cleavages are carried out by methods known to those skilled in the art. The reaction is carried out in a suitable solvent as indicated above, preferably by the addition of boron tribromide. The reaction is most preferably carried out in dichloromethane at a reaction temperature between about -30 ° and 50 °, normally between -20 ° and 20 °, more preferably between about -15 ° and about 0 °.
Weiterhin bevorzugt ist die Herstellung der Verbindungen der Formel I durch Umsetzung einer Verbindung der Formel IV mit einem 1 ,3-Preference is furthermore given to preparing the compounds of the formula I by reacting a compound of the formula IV with a 1, 3
Bis(trialkylsilyl)carbodiimid [Alkyl bedeutet vorzugsweise C1 , C2, C3 oderBis (trialkylsilyl) carbodiimide [alkyl is preferably C1, C2, C3 or
C4 Alkyl), wie z.B. N,N'-Bis(thmethylsilyl)carbodiimid. Die Umsetzung erfolgt in einem geeigneten Lösungsmittel, vorzugsweise THF, und bei Temperaturen zwischen 10 und 500C. Die Verbindungen der Formel IV R1 C4 alkyl), such as N, N'-bis (thmethylsilyl) carbodiimide. The reaction is carried out in a suitable solvent, preferably THF, and at temperatures between 10 and 50 ° C. The compounds of the formula IV R 1
sind neu und werden wie folgt hergestellt: are new and are made as follows:
Die Umsetzungen erfolgen analog: a) A. Franke; Liebigs Annalen der Chemie (1982), (4), 794-804. b) J. Hlavac et al; J. Heterocyclic Chem. (2004), 41(4), 33-636The reactions are carried out analogously: a) A. Franke; Liebigs Annalen der Chemie (1982), (4), 794-804. b) J. Hlavac et al; J. Heterocyclic Chem. (2004), 41 (4), 33-636
Gegenstand der Erfindung sind daher auch die Verbindungen der Formel IVThe invention therefore also relates to the compounds of the formula IV
R1 R 1
worin R1 H, A, (CHa)nCONH2, (CH2)nCONHA, (CH2)HCONAA1, HaI, wherein R 1 is H, A, (CH 3) n CONH 2 , (CH 2 ) n CONHA, (CH 2 ) H CONAA 1 , Hal,
(CH2)nNH2, (CH2)nNHA, (CHz)nNAA', CN, NO2, (CH2y\r, OAr, (CH2)nCOOH, (CH2)nCOOA, (CH2)nOH, (CH2)nOA, (CH2)nHet, COHet, C≡C-CH2SiA2A', C≡CH, C≡C-A, CH=CH-Ar1 , CH=CH-COOA, CH2CH(OH)CH2OH, O(CH2)nOH, NH(CH2)nOH, O(CH2)nOA, NH(CH2)nOA, O(CH2)nNHA, NH(CH2)nNHA, NR4R5, (CH2)nCOOA, (CH2)nCONH(CH2)2CN, NH(CH2)nAr oder CH=CH-COOH, R2 H, A, (CH2)nAr, (CH2)nHet, (CH2)nOH, (CH2)nOA, (CH2)nNHHet, (CH2)nSA oder (CH2)nCH(OH)Ar, R3 A, (CH2)nAr, (CH2)nHet, (CH2)nCN, (CH2)nNH2, (CH2)nNHA,(CH 2 ) n NH 2 , (CH 2 ) n NHA, (CHz) n NAA ', CN, NO 2 , (CH 2 y \ r, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het, COHet, C≡C-CH 2 SiA 2 A ', C≡CH, C≡CA, CH = CH-Ar 1 , CH = CH-COOA, CH 2 CH (OH) CH 2 OH, O (CH 2 ) n OH, NH (CH 2 ) n OH, O (CH 2 ) n OA, NH (CH 2 ) n OA, O (CH 2 ) n NHA, NH (CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH (CH 2 ) 2 CN, NH (CH 2 ) n Ar or CH = CH- COOH, R 2 H, A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NHHet, (CH 2 ) n SA or (CH 2 ) n CH (OH) Ar, R 3 A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n CN, (CH 2 ) n NH 2 , (CH 2 ) n NHA,
(CH2)nNAA', (CH2)nOH, (CH2)nOA oder (CH2)nNHHet, R2 und R3 zusammen mit dem N-Atom an das sie gebunden sind, auch einen unsubstituierten oder ein-, zwei- oder dreifach durch HaI, A, (CH2)nOH, (CH2)nOA und/oder =0(CH 2 ) n NAA ', (CH 2 ) n OH, (CH 2 ) n OA or (CH 2 ) n NHHet, R 2 and R 3 together with the N-atom to which they are attached, also an unsubstituted or one, two or three times by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and / or = 0
(Carbonylsauerstoff) substituierten gesättigten, ungesättigten oder aromatischen mono- oder bicyclischen Heterocyclus, der weitere 1 bis 3 N-, O- und/oder S-Atome enthalten kann, R4, R5 jeweils unabhängig voneinander (CH2)nOH, (CH2)nOA,(Carbonyl oxygen) substituted saturated, unsaturated or aromatic mono- or bicyclic heterocycle which may contain another 1 to 3 N, O and / or S atoms, R 4 , R 5 are each independently (CH 2 ) n OH, ( CH 2 ) n OA,
(CH2)nNH2, (CH2)nNHA oder (CHz)nNAA1,(CH 2 ) n NH 2 , (CH 2 ) n NHA or (CHz) n NAA 1 ,
Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI, (CH2)nOA, (CH2)nOH, (CHz)nCN, SA, SOA, SO2A, NO2, C≡CH, (CH2)nCOOH, CHO, (CH2)nCOOA,Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, (CH 2 ) n OA, (CH 2 ) n OH, (CHz) n CN, SA, SOA, SO 2 A, NO 2 , C≡CH, (CH 2 ) n COOH, CHO, (CH 2 ) n COOA,
CONH2, CONHA, CONAA1, NHCOA, CH(OH)A, (CH2)nNH2, (CH2)nNHA, (CHz)nNAA1, (CHz)nNAAr1, O(CH2)nHet1, (CH2)nHet1, COO(CHz)nAr1, (CHz)nNHSO2A, (CH2)nOAr1, 0(CHz)nAr1, SO2NH(CHz)nNH2, SO2NH2, SO2NHA, SO2NAA1, CONHAr1, CONH(CHz)nCOOA, CONH(CHz)nCOOH,CONH 2 , CONHA, CONAA 1 , NHCOA, CH (OH) A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CHz) n NAA 1 , (CHz) n NAAr 1 , O (CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO (CHz) n Ar 1 , (CHz) n NHSO 2 A, (CH 2 ) n OAr 1 , 0 (CHz) n Ar 1 , SO 2 NH (CHz) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 , CONHAr 1 , CONH (CHz) n COOA, CONH (CHz) n COOH,
NHCO(CHz)nCOOA, NHCO(CHz)nCOOH1 CONH(CHz)nNH2, CONH(CHz)nNHA, CONH(CHz)nNAA1, CONH(CHz)nCN, NHCOHet, SO2Het, COHet und/oder (CHz)nCH(NH2)COOH substituiertes Phenyl, Naphthyl, Tetrahydronaphthyl oderNHCO (CHz) n COOA, NHCO (CHz) n COOH 1 CONH (CHz) n NH 2 , CONH (CHz) n NHA, CONH (CHz) n NAA 1 , CONH (CHz) n CN, NHCOHet, SO 2 Het, COHet and / or (CHz) n CH (NH 2 ) COOH substituted phenyl, naphthyl, tetrahydronaphthyl or
Biphenyl,biphenyl,
Ar1 unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI und/oder OA substituiertes Phenyl, Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S- Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch A, (CH2)nOA, (CH2)nOH, Ar1, SH, S(O)1nA, HaI, NO2, CN1 COA, CHO, COOA, COOBenzyl, CONH2, CONHA, CONAA1, SO2NH2, (CHz)nNH2, (CHz)nNHA, (CHz)nNAA1, NHSO2A und/oder =O (Carbonylsauerstoff) substituiert sein kann, Het1 einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S- 5Ar 1 is unsubstituted or mono-, di-, tri-, tetra- or quintuply phenyl substituted by A, Hal and / or OA, Het is a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and or S atoms which are unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S (O) 1n A, Hal, NO 2 , CN 1 COA, CHO, COOA, COOBenzyl, CONH 2 , CONHA, CONAA 1 , SO 2 NH 2 , (CHz) n NH 2 , (CHz) n NHA, (CHz) n NAA 1 , NHSO 2 A and / or = O (carbonyl oxygen), Het 1 is a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N-, O- and / or S-5
Atomen, der unsubstituiert oder ein- oder zweifach durch A,Atoms that are unsubstituted or one or two times A,
OA, OH, HaI, CN und/oder =O (Carbonylsauerstoff) substituiert sein kann, A, A' jeweils unabhängig voneinander unverzweigtes oderOA, OH, Hal, CN and / or = O (carbonyl oxygen) may be substituted, A, A 'each independently of one another unbranched or
10 verzweigtes Alkyl mit 1-10 C-Atomen, worin 1-3 nichtbenachbarte CH2-Gruppen durch O, S, SO, SO2, NH, NMe oder NEt und/oder auch 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können,10 branched alkyl having 1-10 C atoms, wherein 1-3 are non-adjacent CH 2 groups by O, S, SO, SO 2 , NH, NMe or NEt and / or 1-5 H atoms by F, OH and / or Cl can be replaced,
^ 5 Alk1, cyclisches Alkyl mit 3-8 C-Atomen oder^ 5 Alk 1 , cyclic alkyl having 3-8 C atoms or
Cycloalkylalkylen, worin 1-5 H-Atome durch F1 OH und/oder Cl ersetzt sein können, Alk1 Alkenyl oder Alkinyl mit 2-6 C-Atomen, m O, 1 oder 2,Cycloalkylalkylene in which 1-5 H atoms may be replaced by F 1 OH and / or Cl, Alk 1 is alkenyl or alkynyl having 2-6 C atoms, m is O, 1 or 2,
20 n 0, 1 , 2, 3 oder 4, bedeuten, sowie deren Salze.20 n is 0, 1, 2, 3 or 4, and their salts.
25 Bevorzugt sind Verbindungen der Formel IV, worinPreference is given to compounds of the formula IV in which
R1 H, A, (CH2)nCONH2, (CH2)nCONHA, (CH2)nCONAA', HaI,R 1 is H, A, (CH 2 ) n CONH 2 , (CH 2 ) n CONHA, (CH 2 ) n CONAA ', Hal,
(CH2)nNH2, (CH2)nNHA, (CH2)nNAA\ CN, NO2, (CH2)nAr, OAr, (CH2)nCOOH, (CH2)nCOOA, (CH2)nOH, (CH2)nOA, (CH2)nHet,(CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA \ CN, NO 2 , (CH 2 ) n Ar, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA, ( CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het,
3Q COHet, C≡C-CH2SiA2A\ C≡CH, C≡C-A, CH=CH-Ar1, 3Q COHet, C≡C-CH 2 SiA 2 A \ C≡CH, C≡CA, CH = CH-Ar 1 ,
CH=CH-COOA, CH2CH(OH)CH2OH, O(CH2)nOH, NH(CH2)nOH,CH = CH-COOA, CH 2 CH (OH) CH 2 OH, O (CH 2 ) n OH, NH (CH 2 ) n OH,
O(CH2)nOA, NH(CH2)nOA, O(CH2)nNHA, NH(CH2)nNHA, NR4R5, (CH2)nCOOA, (CH2)nCONH(CH2)2CN, NH(CH2)nArO (CH 2 ) n OA, NH (CH 2 ) n OA, O (CH 2 ) n NHA, NH (CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH (CH 2 ) 2 CN, NH (CH 2 ) n Ar
35 oder CH=CH-COOH, R2 H, Methyl, Ethyl, 2-Hydroxyethyl, 2-Methoxyethyl, 2-(Pyridin- 35 or CH = CH-COOH, R 2 is H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2- (pyridine)
2-ylamino)-ethyl oder Benzyl, R3 Methyl, Ethyl, Propyl, Butyl, Isopropyl, Phenyl, Benzyl, Furyl-2-ylamino) -ethyl or benzyl, R 3 is methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl, furyl
2-ylmethyl, HC≡C-CH2-, 2-Methoxy-ethyl, 3-Trifluormethyl- benzyl, Pyridin-2- oder 3-ylmethyl, 2-, 3- oder 4-Fluor-benzyl,2-ylmethyl, HC≡C-CH 2 -, 2-methoxyethyl, 3-trifluoromethylbenzyl, pyridin-2 or 3-ylmethyl, 2-, 3- or 4-fluorobenzyl,
2-, 3- oder 4-Methoxy-benzyl, 2-, 3- oder 4-Methylbenzyl, 3- Chlor-6-methoxy-benzyl, N,N-Dimethylamino-carbonylmethyl, 4-([1 ,2,4]Triazol-1-ylmethyl)-benzyl, 2- oder 3-(Pyridin-3-yl)- benzyl, 3-(2-Morpholin-4-yl-ethoxy)-benzyl, 4-(Triazol-1-yl)- benzyl, 3-(Morpholin-4-yl)-benzyl, 3-(Pyrimidin-5-yl)-benzyl, 3- (Morpholin-4-ylmethyl)-benzyl, Cyclopropylmethyl, 2- Cyanethyl, 2-Dimethylamino-ethyl, Cyclohexyl, 3- oder 4- (Methylsulfonylamino)-benzyl, 4-(Methylsulfonylamino- methyl)-benzyl, Benzo[1 ,4]dioxan-6-ylmethyl, Morpholin-4-yl, 2-Hydroxyethyl, 2-Methoxyethyl, 1 ,3,5-Trimethyl-1 H-pyrazol- 4-ylmethyl, 2-Methylsulfanil-ethyl, 2-Hydroxy-2-phenyl-ethyl,2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-methylbenzyl, 3-chloro-6-methoxybenzyl, N, N-dimethylamino-carbonylmethyl, 4 - ([1, 2,4] Triazol-1-ylmethyl) benzyl, 2- or 3- (pyridin-3-yl) benzyl, 3- (2-morpholin-4-yl-ethoxy) -benzyl, 4- (triazol-1-yl) - benzyl, 3- (morpholin-4-yl) benzyl, 3- (pyrimidin-5-yl) benzyl, 3- (morpholin-4-ylmethyl) benzyl, cyclopropylmethyl, 2-cyanoethyl, 2-dimethylamino-ethyl, Cyclohexyl, 3- or 4- (methylsulfonylamino) -benzyl, 4- (methylsulfonylamino-methyl) -benzyl, benzo [1,4] dioxan-6-ylmethyl, morpholin-4-yl, 2-hydroxyethyl, 2-methoxyethyl, 1 , 3,5-trimethyl-1H-pyrazol-4-ylmethyl, 2-methylsulfanil-ethyl, 2-hydroxy-2-phenyl-ethyl,
2-(N-Ethyl-N-methyl-amino)-ethyl, 2-Diethylamino-ethyl, 1-2- (N-ethyl-N-methylamino) ethyl, 2-diethylamino-ethyl, 1-
Methyl-1 H-pyrazol-3-yl, Chinolin-5- oder 8-yl, 2-Methyl-1H-pyrazol-3-yl, quinoline-5 or 8-yl, 2-
Methylsulfanil-phenyl, Biphenyl-2-yl, 5,6,7,8-Tetrahydro- naphthalin-1-yl, 2-(1 H-Benzimidazol-2-yl)-phenyl, 3,4,5- Trimethoxy-phenyl, 2-Ethinylphenyl oder 1-Methyl-5- trifluormethyl-1 H-indazol-3-yl,Methylsulfanilphenyl, biphenyl-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 2- (1H-benzimidazol-2-yl) -phenyl, 3,4,5-trimethoxyphenyl , 2-ethynylphenyl or 1-methyl-5-trifluoromethyl-1H-indazol-3-yl,
R2 und R3 zusammen mit dem N-Atom an das sie gebunden sind, auch unsubstituiertes oder ein-, zwei- oder dreifach durch HaI, A, (CH2)nOH, (CH2)nOA und/oder =O (Carbonylsauerstoff) substituiertes 1 ,3-Dihydro-isoindolyl, Azepanyl, Pyrrolidinyl,R 2 and R 3 together with the N-atom to which they are attached, also unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and / or = O (Carbonyl oxygen) substituted 1,3-dihydro-isoindolyl, azepanyl, pyrrolidinyl,
Piperazinyl, Piperidinyl oder Morpholinyl, R4, R5 jeweils unabhängig voneinander (CH2)nOH, (CH2)nOA,Piperazinyl, piperidinyl or morpholinyl, R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
(CH2)nNH2, (CH2)nNHA oder (CH2)nNAAr,(CH 2 ) n NH 2 , (CH 2 ) n NHA or (CH 2 ) n NAA r ,
Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI, (CH2)nOA, (CH2)nOH, (CH2)nCN, SA, SOA, SO2A, NO2, C≡CH, (CH2)nCOOH, CHO, (CH2)nCOOA, CONH2, CONHA, CONAA1, NHCOA, CH(OH)A, (CH2)nNH2, (CH2)nNHA, (CH2)RNAA1, (CH2)nNAAr1, O(CH2)nHet1, (CH2)nHet1, COO(CH2)nAr1, (CH2)nNHSO2A, (CH2)nOAr1, O(CH2)nAr1, SO2NH(CH2)nNH2, SO2NH2, SO2NHA, SO2NAA1, CONHAr1, CONH(CH2)nCOOA, CONH(CH2)nCOOH,Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, (CH 2 ) n OA, (CH 2 ) n OH, (CH 2 ) n CN, SA, SOA, SO 2 A, NO 2 , C≡CH, (CH 2 ) n COOH, CHO, (CH 2 ) n COOA, CONH 2 , CONHA, CONAA 1 , NHCOA, CH (OH) A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) RNAA 1 , (CH 2 ) n NAAr 1 , O (CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO (CH 2 ) n Ar 1 , (CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 , O (CH 2 ) n Ar 1 , SO 2 NH (CH 2 ) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 , CONHAr 1 , CONH (CH 2 ) n COOA, CONH (CH 2 ) n COOH,
NHCO(CH2)nCOOA, NHCO(CH2)nCOOH, CONH(CH2)nNH2, CONH(CH2)nNHA, CONH(CH2)nNAA', CONH(CH2)nCN, NHCOHet, SO2Het, COHet und/oder (CH2JnCH(NH2)COOH substituiertes Phenyl, Naphthyl, Tetrahydronaphthyl oderNHCO (CH 2 ) n COOA, NHCO (CH 2 ) n COOH, CONH (CH 2 ) n NH 2 , CONH (CH 2 ) n NHA, CONH (CH 2 ) n NAA ', CONH (CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and / or (CH 2 J n CH (NH 2 ) COOH substituted phenyl, naphthyl, tetrahydronaphthyl or
Biphenyl,biphenyl,
Ar1 unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI und/oder OA substituiertes Phenyl, Het unsubstituiertes oder ein-, zwei- oder dreifach durch HaI,Ar 1 is unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl substituted by A, Hal and / or OA, H is unsubstituted or mono-, di- or trisubstituted by Hal,
Phenyl, A, (CH2)nOH, (CH2)nOA, COOH, COOA, COOBenzyl, CN, COA, CHO, (CH2)nNH2, (CH2)nNHA, (CH2)nNAA' und/oder =0 (Carbonylsauerstoff) substituiertes Pyridyl,Phenyl, A, (CH 2 ) n OH, (CH 2 ) n OA, COOH, COOA, COOBenzyl, CN, COA, CHO, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA 'and / or = O (carbonyl oxygen) substituted pyridyl,
Pyrimidinyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Pyrazolyl,Pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,
Triazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Benzothiazolyl,Triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl,
Benzo[1 ,4]dioxanyl, Chinolyl, Isochinolyl, Chinazolinyl, Benzimidazolyl, Indazolyl, Indolyl, 1 ,3-Dihydro-isoindolyl, Benzofuranyl, Dihydro-benzofuranyl, Benzo[1 ,3]dioxolyl, Piperazinyl, Pyrazinyl, Pyridazinyl, Morpholinyl, Azepanyl,Benzo [1,4] dioxanyl, quinolyl, isoquinolyl, quinazolinyl, benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzofuranyl, benzo [1,3] dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl,
Pyrrolidinyl oder Piperidinyl,Pyrrolidinyl or piperidinyl,
Het1 unsubstituiertes oder einfach durch =0 (Carbonylsauerstoff) substituiertes Morpholinyl, Piperidinyl oder Pyrrolidinyl, A, A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-6 C-Atomen, worin 1-2 CH2-Gruppen durch O, NH und/oder NMe und/oder auch 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können, oder cyclisches Alkyl mit 3-8 C-Atomen, worin 1-3 H-Atome durchHet 1 unsubstituted or simply by = 0 (carbonyl oxygen) substituted morpholinyl, piperidinyl or pyrrolidinyl, A, A 'each independently of one another unbranched or branched alkyl having 1-6 C atoms, wherein 1-2 CH 2 groups by O, NH and or NMe and / or 1-5 H atoms may be replaced by F, OH and / or Cl, or cyclic alkyl having 3-8 C atoms, wherein 1-3 H atoms by
OH ersetzt sein können, m 0, 1 oder 2, n 0, 1 oder 2, bedeuten, sowie deren Salze. 5OH can be replaced, m is 0, 1 or 2, n is 0, 1 or 2, and their salts. 5
Die Bedeutungen sowie die bevorzugten Bedeutungen der angegebenen Reste sind die, wie für die Verbindungen der Formel I oben angegeben.The meanings as well as the preferred meanings of the radicals indicated are those as given above for the compounds of the formula I.
10 Pharmazeutische Salze und andere Formen10 Pharmaceutical salts and other forms
Die genannten erfindungsgemäßen Verbindungen lassen sich in ihrer endgültigen Nichtsalzform verwenden. Andererseits umfaßt die vorliegende Erfindung auch die Verwendung dieser Verbindungen in Form ihrerThe abovementioned compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of theirs
* c pharmazeutisch unbedenklichen Salze, die von verschiedenen organischen und anorganischen Säuren und Basen nach fachbekannten Vorgehensweisen abgeleitet werden können. Pharmazeutisch unbedenkliche Salzformen der erfindungsgemäßen Verbindungen werden größtenteils konventionell hergestellt. Sofern die erfindungsgemäße Verbindung eine * c pharmaceutically acceptable salts which may be derived from various organic and inorganic acids and bases by art-known procedures. Pharmaceutically acceptable salt forms of the compounds of the invention are mostly prepared conventionally. If the compound of the invention a
2020
Carbonsäuregruppe enthält, läßt sich eines ihrer geeigneten Salze dadurch bilden, daß man die Verbindung mit einer geeigneten Base zum entsprechenden Basenadditionssalz umsetzt. Solche Basen sind zum Beispiel Alkalimetallhydroxide, darunter Kaliumhydroxid, NatriumhydroxidContaining carboxylic acid group, one of their suitable salts can be formed by reacting the compound with a suitable base to the corresponding base addition salt. Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide
25 und Lithiumhydroxid; Erdalkalimetallhydroxide wie Bariumhydroxid und Calciumhydroxid; Alkalimetallalkoholate, z.B. Kaliumethanolat und Natriumpropanolat; sowie verschiedene organische Basen wie Piperidin, Diethanolamin und N-Methylglutamin. Die Aluminiumsalze der Verbindun-25 and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds
30 gen der Formel I zählen ebenfalls dazu. Bei bestimmten Verbindungen der Formel I lassen sich Säureadditionssalze dadurch bilden, daß man diese Verbindungen mit pharmazeutisch unbedenklichen organischen und anorganischen Säuren, z.B. Halogenwasserstoffen wie Chlorwasserstoff, 30 gene of formula I are also included. In certain compounds of the formula I, acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride,
Bromwasserstoff oder Jodwasserstoff, anderen Mineralsäuren und ihrenHydrogen bromide or hydrogen iodide, other mineral acids and their
35 entsprechenden Salzen wie Sulfat, Nitrat oder Phosphat und dergleichen sowie Alkyl- und Monoarylsulfonaten wie Ethansulfonat, Toluolsulfonat und 4635 corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and 46
- 47 -- 47 -
Benzolsulfonat, sowie anderen organischen Säuren und ihren entsprechenden Salzen wie Acetat, Trifluoracetat, Tartrat, Maleat, Succinat, Citrat, Benzoat, Salicylat, Ascorbat und dergleichen behandelt. Dementsprechend zählen zu pharmazeutisch unbedenklichen Säureadditions- salzen der Verbindungen der Formel I die folgenden: Acetat, Adipat,Benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate,
Alginat, Arginat, Aspartat, Benzoat, Benzolsulfonat (Besylat), Bisulfat, Bisulfit, Bromid, Butyrat, Kampferat, Kampfersulfonat, Caprylat, Chlorid, Chlorbenzoat, Citrat, Cyclopentanpropionat, Digluconat, Dihydrogen- phosphat, Dinitrobenzoat, Dodecylsulfat, Ethansulfonat, Fumarat,Alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate,
Galacterat (aus Schleimsäure), Galacturonat, Glucoheptanoat, Gluconat, Glutamat, Glycerophosphat, Hemisuccinat, Hemisulfat, Heptanoat, Hexanoat, Hippurat, Hydrochlorid, Hydrobromid, Hydroiodid, 2-Hydroxy- ethansulfonat, lodid, Isethionat, Isobutyrat, Lactat, Lactobionat, Malat, Maleat, Malonat, Mandelat, Metaphosphat, Methansulfonat, Methylbenzoat, Monohydrogenphosphat, 2-Naphthalinsulfonat, Nicotinat, Nitrat, Oxalat, Oleat, Palmoat, Pectinat, Persulfat, Phenylacetat, 3- Phenylpropionat, Phosphat, Phosphonat, Phthalat, was jedoch keine Einschränkung darstellt.Galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, Maleate, malonate, mandelate, metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.
Weiterhin zählen zu den Basensalzen der erfindungsgemäßen Verbindungen Aluminium-, Ammonium-, Calcium-, Kupfer-, Eisen(lll)-, Eisen(ll)-, Lithium-, Magnesium-, Mangan(lll)-, Mangan(ll), Kalium-,Furthermore, the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium -
Natrium- und Zinksalze, was jedoch keine Einschränkung darstellen soll. Bevorzugt unter den oben genannten Salzen sind Ammonium; die Alkalimetallsalze Natrium und Kalium, sowie die Erdalkalimetalsalze Calcium und Magnesium. Zu Salzen der erfindungsgemäßenSodium and zinc salts, but this is not intended to be limiting. Preferred among the above salts are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium. To salts of the invention
Verbindungen, die sich von pharmazeutisch unbedenklichen organischen nicht-toxischen Basen ableiten, zählen Salze primärer, sekundärer und tertiärer Amine, substituierter Amine, darunter auch natürlich vorkommender substituierter Amine, cyclischer Amine sowie basischer lonenaustauscherharze, z.B. Arginin, Betain, Koffein, Chlorprocain, Cholin,Compounds derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, e.g. Arginine, betaine, caffeine, chloroprocaine, choline,
N.N'-Dibenzylethylendiamin (Benzathin), Dicyclohexylamin, Diethanolamin, Diethylamin, 2-Diethylaminoethanol, 2-Dimethylaminoethanol, Ethanolamin, Ethylendiamin, N-Ethylmorpholin, N-Ethylpiperidin, Glucamin, Glucosamin, Histidin, Hydrabamin, Iso-propylamin, Lidocain,N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, Diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine,
Lysin, Meglumin, N-Methyl-D-glucamin, Morpholin, Piperazin, Piperidin,Lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine,
Polyaminharze, Procain, Purine, Theobromin, Triethanolamin,Polyamine resins, procaine, purines, theobromine, triethanolamine,
Triethylamin, Trimethylamin, Tripropylamin sowie Tris-(hydroxymethyl)- methylamin (Tromethamin), was jedoch keine Einschränkung darstellen soll.Triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl) - methylamine (tromethamine), but this is not intended to be limiting.
Verbindungen der vorliegenden Erfindung, die basische stickstoffhaltige Gruppen enthalten, lassen sich mit Mitteln wie (Ci-C4) Alkylhalogeniden, z.B. Methyl-, Ethyl-, Isopropyl- und tert.-Butylchlorid, -bromid und -iodid; Di(Ci-C4)Alkylsulfaten, z.B. Dimethyl-, Diethyl- und Diamylsulfat; (C10- Ci8)Alkylhalogeniden, z.B. Decyh Dodecyl-, Lauryl-, Myristyl- und Stearylchlorid, -bromid und -iodid; sowie Aryl-(Ci-C4)Alkylhalogeniden, z.B. Benzylchlorid und Phenethylbromid, quarternisieren. Mit solchen Salzen können sowohl wasser- als auch öllösliche erfindungsgemäßeCompounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C 4 ) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -C 4 ) alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C 10 - C 8) alkyl halides, for example Decyh dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl- (C 1 -C 4 ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize. With such salts, both water-soluble and oil-soluble according to the invention
Verbindungen hergestellt werden.Connections are made.
Zu den oben genannten pharmazeutischen Salzen, die bevorzugt sind, zählen Acetat, Trifluoracetat, Besylat, Citrat, Fumarat, Gluconat, Hemisuccinat, Hippurat, Hydrochlorid, Hydrobromid, Isethionat, Mandelat, Meglumin, Nitrat, Oleat, Phosphonat, Pivalat, Natriumphosphat, Stearat, Sulfat, Sulfosalicylat, Tartrat, Thiomalat, Tosylat und Tromethamin, was jedoch keine Einschränkung darstellen soll.Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, Sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, which is not intended to be limiting.
Die Säureadditionssalze basischer erfindungsgemäßer Verbindungen werden dadurch hergestellt, daß man die freie Basenform mit einer ausreichenden Menge der gewünschten Säure in Kontakt bringt, wodurch man auf übliche Weise das Salz darstellt. Die freie Base läßt sich durch In-The acid addition salts of basic compounds of this invention are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base can be determined by
Kontakt-Bringen der Salzform mit einer Base und Isolieren der freien Base auf übliche Weise regenerieren. Die freien Basenformen unterscheiden sich in gewissem Sinn von ihren entsprechenden Salzformen in bezug auf bestimmte physikalische Eigenschaften wie Löslichkeit in polaren Lösungsmitteln; im Rahmen der Erfindung entsprechen die Salze jedoch sonst ihren jeweiligen freien Basenformen. 5Contacting the salt form with a base and isolating the free base in the usual way regenerate. Distinguish the free base forms in a sense, of their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms. 5
Wie erwähnt werden die pharmazeutisch unbedenklichen Basenadditionssalze der erfindungsgemäßen Verbindungen mit Metallen oder Aminen wie Alkalimetallen und Erdalkalimetallen oder organischen Aminen gebildet. 10 Bevorzugte Metalle sind Natrium, Kalium, Magnesium und Calcium. Bevorzugte organische Amine sind N.N'-Dibenzylethylendiamin, Chlorprocain, Cholin, Diethanolamin, Ethylendiamin, N-Methyl-D-glucamin und Procain.As mentioned, the pharmaceutically acceptable base addition salts of the compounds of the invention are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
,. C Die Basenadditionssalze von erfindungsgemäßen sauren Verbindungen werden dadurch hergestellt, daß man die freie Säureform mit einer ausreichenden Menge der gewünschten Base in Kontakt bringt, wodurch man das Salz auf übliche Weise darstellt. Die freie Säure läßt sich durch. C The base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid can be passed through
In-Kontakt-Bringen der Salzform mit einer Säure und Isolieren der freienContact the salt form with an acid and isolate the free
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Säure auf übliche Weise regenerieren. Die freien Säureformen unterscheiden sich in gewissem Sinn von ihren entsprechenden Salzformen in bezug auf bestimmte physikalische Eigenschaften wie Löslichkeit in polaren Lösungsmitteln; im Rahmen der Erfindung entsprechen die SalzeRegenerate acid in the usual way. The free acid forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; in the context of the invention, the salts correspond
25 jedoch sonst ihren jeweiligen freien Säureformen.25 but otherwise their respective free acid forms.
Enthält eine erfindungsgemäße Verbindung mehr als eine Gruppe, die solche pharmazeutisch unbedenklichen Salze bilden kann, so umfaßt die 30 Erfindung auch mehrfache Salze. Zu typischen mehrfachen Salzformen zählen zum Beispiel Bitartrat, Diacetat, Difumarat, Dimeglumin, Diphosphat, Dinatrium und Trihydrochlorid, was jedoch keine Einschränkung darstellen soll.Contains a compound of the invention more than one group capable of forming pharmaceutically acceptable salts, the 30 invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
3535
Im Hinblick auf das oben Gesagte sieht man, daß unter dem AusdruckIn view of the above, one sees that under the expression
"pharmazeutisch unbedenkliches Salz" im vorliegenden Zusammenhang 04846"pharmaceutically acceptable salt" in the present context 04846
- 50 -- 50 -
ein Wirkstoff zu verstehen ist, der eine erfindungsgemäße Verbindung in der Form eines ihrer Salze enthält, insbesondere dann, wenn diese Salzform dem Wirkstoff im Vergleich zu der freien Form des Wirkstoffs oder irgendeiner anderen Salzform des Wirkstoffs, die früher verwendet wurde, verbesserte pharmakokinetische Eigenschaften verleiht. Die pharmazeutisch unbedenkliche Salzform des Wirkstoffs kann auch diesem Wirkstoff erst eine gewünschte pharmakokinetische Eigenschaft verleihen, über die er früher nicht verfügt hat, und kann sogar die Pharmakodynamik dieses Wirkstoffs in bezug auf seine therapeutische Wirksamkeit im Körper positiv beeinflussen.is an active ingredient containing a compound of the invention in the form of one of its salts, especially when this salt form imparts to the active ingredient improved pharmacokinetic properties as compared to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used , The pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the body.
Erfindungsgemäße Verbindungen können aufgrund ihrer Molekülstruktur chiral sein und können dementsprechend in verschiedenen enantiomeren Formen auftreten. Sie können daher in racemischer oder in optisch aktiver Form vorliegen.Compounds of the invention may be chiral due to their molecular structure and accordingly may occur in various enantiomeric forms. They may therefore be in racemic or optically active form.
Da sich die pharmazeutische Wirksamkeit der Racemate bzw. der Stereo- isomeren der erfindungsgemäßen Verbindungen unterscheiden kann, kann es wünschenswert sein, die Enantiomere zu verwenden. In diesen Fällen kann das Endprodukt oder aber bereits die Zwischenprodukte in enantiomere Verbindungen, durch dem Fachmann bekannte chemische oder physikalische Maßnahmen, aufgetrennt oder bereits als solche bei der Synthese eingesetzt werden.Since the pharmaceutical activity of the racemates or of the stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or else the intermediates may already be separated into enantiomeric compounds, chemical or physical measures known to those skilled in the art, or already be used as such in the synthesis.
Im Falle racemischer Amine werden aus dem Gemisch durch Umsetzung mit einem optisch aktiven Trennmittel Diastereomere gebildet. Als Trenn- mittel eignen sich z.B. optisch aktiven Säuren, wie die R- und S-Formen von Weinsäure, Diacetylweinsäure, Dibenzoylweinsäure, Mandelsäure, Äpfelsäure, Milchsäure, geeignet N-geschützte Aminosäuren (z.B. N-Ben- zoylprolin oder N-Benzolsulfonylprolin) oder die verschiedenen optisch aktiven Camphersulfonsäuren. Vorteilhaft ist auch eine chromatographische Enantiomerentrennung mit Hilfe eines optisch aktiven Trenn- mittels (z.B. Dinitrobenzoylphenylglycin, Cellulosetriacetat oder andere Derivate von Kohlenhydraten oder auf Kieselgel fixierte chiral derivatisierte Methacrylatpolymere). Als Laufmittel eignen sich hierfür wäßrige oder alkoholische Lösungsmittelgemische wie z.B. Hexan/Isopropanol/ Acetonitril z.B. im Verhältnis 82:15:3.In the case of racemic amines diastereomers are formed from the mixture by reaction with an optically active release agent. Suitable release agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulphonylproline) or the different optically active camphorsulfonic acids. Also advantageous is a chromatographic separation of enantiomers by means of an optically active separation by means of (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or silica-gel-fixed chirally derivatized methacrylate polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile, for example in the ratio 82: 15: 3.
Gegenstand der Erfindung ist ferner die Verwendung der Verbindungen und/oder ihrer physiologisch unbedenklichen Salze zur Herstellung eines Arzneimittels (pharmazeutische Zubereitung), insbesondere auf nichtchemischem Wege. Hierbei können sie zusammen mit mindestens einem festen, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoffen in eine geeignete Dosierungsform gebracht werden.The invention further provides the use of the compounds and / or their physiologically acceptable salts for the preparation of a pharmaceutical preparation (pharmaceutical preparation), in particular by a non-chemical route. In this case, they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or excipient and optionally in combination with one or more further active ingredients.
Gegenstand der Erfindung sind ferner Arzneimittel, enthaltend mindestens eine erfindungsgemäße Verbindung und/oder ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.The invention furthermore relates to medicaments comprising at least one compound according to the invention and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
Pharmazeutische Formulierungen können in Form von Dosiseinheiten, die eine vorbestimmte Menge an Wirkstoff pro Dosiseinheit enthalten, dargereicht werden. Eine solche Einheit kann beispielsweise 0,1 mg bis 3 g, vorzugsweise 1 mg bis 700 mg, besonders bevorzugt 5 mg bis 100 mg einer erfindungsgemäßen Verbindung enthalten, je nach dem behandelten Krankheitszustand, dem Verabreichungsweg und dem Alter, Gewicht und Zustand des Patienten, oder pharmazeutische Formulierungen können in Form von Dosiseinheiten, die eine vorbestimmte Menge an Wirkstoff pro Dosiseinheit enthalten, dargereicht werden. Bevorzugte Dosierungs- einheitsformulierungen sind solche, die eine Tagesdosis oder Teildosis, wie oben angegeben, oder einen entsprechenden Bruchteil davon eines Wirkstoffs enthalten. Weiterhin lassen sich solche pharmazeutischen Formulierungen mit einem der im pharmazeutischen Fachgebiet allgemein bekannten Verfahren herstellen.Pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Such a moiety may contain, for example, from 0.1 mg to 3 g, preferably from 1 mg to 700 mg, more preferably from 5 mg to 100 mg of a compound of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof Active ingredient included. Furthermore, such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
Pharmazeutische Formulierungen lassen sich zur Verabreichung über einen beliebigen geeigneten Weg, beispielsweise auf oralem (einschließlich buccalem bzw. sublingualem), rektalem, nasalem, topischem (einschließlich buccalem, sublingualem oder transdermalem), vaginalem oder parenteralem (einschließlich subkutanem, intramuskulärem, intravenösem oder intradermalem) Wege, anpassen. Solche Formulierungen können mit allen im pharmazeutischen Fachgebiet bekannten Verfahren hergestellt werden, indem beispielsweise der Wirkstoff mit dem bzw. den Trägerstoff(en) oder Hilfsstoff(en) zusammengebracht wird.Pharmaceutical formulations may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal). Ways, adapt. Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).
An die orale Verabreichung angepaßte pharmazeutische Formulierungen können als separate Einheiten, wie z.B. Kapseln oder Tabletten; Pulver oder Granulate; Lösungen oder Suspensionen in wäßrigen oder nichtwäßrigen Flüssigkeiten; eßbare Schäume oder Schaumspeisen; oder ÖI-in-Wasser-Flüssigemulsionen oder Wasser-in-ÖI-Flüssigemulsionen dargereicht werden.Pharmaceutical formulations adapted for oral administration may be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
So läßt sich beispielsweise bei der oralen Verabreichung in Form einer Tablette oder Kapsel die Wirkstoffkomponente mit einem oralen, nichttoxischen und pharmazeutisch unbedenklichen inerten Trägerstoff, wie z.B. Ethanol, Glycerin, Wasser u.a. kombinieren. Pulver werden hergestellt, indem die Verbindung auf eine geeignete feine Größe zerkleinert und mit einem in ähnlicher Weise zerkleinerten pharmazeutischen Trägerstoff, wie z.B. einem eßbaren Kohlenhydrat wie beispielsweiseThus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be mixed with an oral, non-toxic and pharmaceutically acceptable inert carrier, e.g. Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as
Stärke oder Mannit vermischt wird. Ein Geschmacksstoff, Konservierungs- mittel, Dispersionsmittel und Farbstoff können ebenfalls vorhanden sein. Kapseln werden hergestellt, indem ein Pulvergemisch wie oben beschrieben hergestellt und geformte Gelatinehüllen damit gefüllt werden. Gleit- und Schmiermittel wie z.B. hochdisperse Kieselsäure, Talkum,Starch or mannitol is mixed. A flavor, preservative, dispersant and dye may also be present. Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith. Lubricants and lubricants such as highly disperse silica, talc,
Magnesiumstearat, Kalziumstearat oder Polyethylenglykol in Festform 5 können dem Pulvergemisch vor dem Füllvorgang zugesetzt werden. EinMagnesium stearate, calcium stearate or polyethylene glycol in solid form 5 can be added to the powder mixture before the filling process. One
Sprengmittel oder Lösungsvermittler, wie z.B. Agar-Agar, Kalziumcarbonat oder Natriumcarbonat, kann ebenfalls zugesetzt werden, um die Verfügbarkeit des Medikaments nach Einnahme der Kapsel zu verbessern.Disintegrants or solubilizers, e.g. Agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
1010
Außerdem können, falls gewünscht oder notwendig, geeignete Bindungs-, Schmier- und Sprengmittel sowie Farbstoffe ebenfalls in das Gemisch eingearbeitet werden. Zu den geeigneten Bindemitteln gehören Stärke,In addition, if desired or necessary, suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture. Suitable binders include starch,
*c Gelatine, natürliche Zucker, wie z.B. Glukose oder Beta-Lactose, Süßstoffe aus Mais, natürliche und synthetische Gummi, wie z.B. Akazia, Traganth oder Natriumalginat, Carboxymethylzellulose, Polyethylenglykol, Wachse, u.a. Zu den in diesen Dosierungsformen verwendeten Schmiermitteln gehören Natriumoleat, Natriumstearat, Magnesiumstearat, Natrium- * c gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate , Magnesium stearate, sodium
20 benzoat, Natriumacetat, Natriumchlorid u.a. Zu den Sprengmitteln gehören, ohne darauf beschränkt zu sein, Stärke, Methylzellulose, Agar, Bentonit, Xanthangummi u.a. Die Tabletten werden formuliert, indem beispielsweise ein Pulvergemisch hergestellt, granuliert oder trocken-20 benzoate, sodium acetate, sodium chloride and the like. The disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or drying
25 verpreßt wird, ein Schmiermittel und ein Sprengmittel zugegeben werden und das Ganze zu Tabletten verpreßt wird. Ein Pulvergemisch wird hergestellt, indem die in geeigneter Weise zerkleinerte Verbindung mit einem Verdünnungsmittel oder einer Base, wie oben beschrieben, und25 is pressed, a lubricant and a disintegrant are added and the whole is compressed into tablets. A powder mixture is prepared by treating the appropriately comminuted compound with a diluent or base as described above, and
O0 gegebenenfalls mit einem Bindemittel, wie z.B. Carboxymethylzellulose, einem Alginat, Gelatine oder Polyvinylpyrrolidon, einem Lösungsverlang- samer, wie z.B. Paraffin, einem Resorptionsbeschleuniger, wie z.B. einem quaternären Salz und/oder einem Absorptionsmittel, wie z.B. Bentonit, Optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution initiator, for example paraffin, a absorption accelerator, for example a quaternary salt and / or an absorbent, for example bentonite,
Kaolin oder Dikalziumphosphat, vermischt wird. Das Pulvergemisch läßtKaolin or dicalcium phosphate. The powder mixture leaves
35 sich granulieren, indem es mit einem Bindemittel, wie z.B. Sirup, Stärkepaste, Acadia-Schleim oder Lösungen aus Zellulose- oder Polymer- materialen benetzt und durch ein Sieb gepreßt wird. Als Alternative zur Granulierung kann man das Pulvergemisch durch eine Tablettiermaschine laufen lassen, wobei ungleichmäßig geformte Klumpen entstehen, die in35 granulate by mixing it with a binder, such as syrup, starch paste, Acadia slime or solutions of cellulose or polymer wetted material and pressed through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are formed in
Granulate aufgebrochen werden. Die Granulate können mittels Zugabe 5 von Stearinsäure, einem Stearatsalz, Talkum oder Mineralöl gefettet werden, um ein Kleben an den Tablettengußformen zu verhindern. Das gefettete Gemisch wird dann zu Tabletten verpreßt. Die erfindungsgemäßen Verbindungen können auch mit einem freifließenden inertenGranules are broken up. The granules may be greased by addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The compounds of the invention can also be used with a free-flowing inert
10 Trägerstoff kombiniert und dann ohne Durchführung der Granulierungs- oder Trockenverpressungsschritte direkt zu Tabletten verpreßt werden. Eine durchsichtige oder undurchsichtige Schutzschicht, bestehend aus einer Versiegelung aus Schellack, einer Schicht aus Zucker oder Polymer-Carrier combined and then pressed directly into tablets without performing the granulation or Trockenverpressungsschritte. A transparent or opaque protective layer consisting of a shellac seal, a layer of sugar or polymer
^5 material und einer Glanzschicht aus Wachs, kann vorhanden sein. Diesen Beschichtungen können Farbstoffe zugesetzt werden, um zwischen unterschiedlichen Dosierungseinheiten unterscheiden zu können.^ 5 material and a gloss layer of wax, may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.
Orale Flüssigkeiten, wie z.B. Lösung, Sirupe und Elixiere, können in FormOral fluids, e.g. Solution, syrups and elixirs, can be in shape
20 von Dosierungseinheiten hergestellt werden, so daß eine gegebeneBe prepared 20 of dosage units, so that a given
Quantität eine vorgegebene Menge der Verbindung enthält. Sirupe lassen sich herstellen, indem die Verbindung in einer wäßrigen Lösung mit geeignetem Geschmack gelöst wird, während Elixiere unter VerwendungQuantity contains a given amount of the compound. Syrups can be made by dissolving the compound in an appropriate taste aqueous solution while using elixirs
25 eines nichttoxischen alkoholischen Vehikels hergestellt werden.25 of a non-toxic alcoholic vehicle.
Suspensionen können durch Dispersion der Verbindung in einem nichttoxischen Vehikel formuliert werden. Lösungsvermittler und Emulgiermittel, wie z.B. ethoxylierte Isostearylalkohole und Polyoxyethylensorbitolether,Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,
O0 Konservierungsmittel, Geschmackszusätze, wie z.B. Pfefferminzöl oder natürliche Süßstoffe oder Saccharin oder andere künstliche Süßstoffe, u.a. können ebenfalls zugegeben werden. O0 preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, among others, may also be added.
Die Dosierungseinheitsformulierungen für die orale Verabreichung könnenDosage unit formulations for oral administration may
35 gegebenenfalls in Mikrokapseln eingeschlossen werden. Die Formulierung läßt sich auch so herstellen, daß die Freisetzung verlängert oder retardiert wird, wie beispielsweise durch Beschichtung oder Einbettung von partikulärem Material in Polymere, Wachs u.a.35 are optionally encapsulated in microcapsules. The formulation can also be prepared so that the release is prolonged or retarded For example, by coating or embedding particulate material in polymers, wax, etc.
Die erfindungsgemäßen Verbindungen sowie Salze, Solvate und physiologisch funktionelle Derivate davon lassen sich auch in Form vonThe compounds of the invention and salts, solvates and physiologically functional derivatives thereof can also be in the form of
Liposomenzuführsystemen, wie z.B. kleinen unilamellaren Vesikeln, großen unilamellaren Vesikeln und multilamellaren Vesikeln, verabreichen. Liposomen können aus verschiedenen Phospholipiden, wie z.B. Cholesterin, Stearylamin oder Phosphatidylcholinen, gebildet werden.Liposome delivery systems, such as e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be prepared from various phospholipids, such as e.g. Cholesterol, stearylamine or phosphatidylcholines.
Die erfindungsgemäßen Verbindungen sowie die Salze, Solvate und physiologisch funktionellen Derivate davon können auch unter Verwendung monoklonaler Antikörper als individuelle Träger, an die die Verbindungsmoleküle gekoppelt werden, zugeführt werden. Die Verbindungen können auch mit löslichen Polymeren als zielgerichtete Arzneistoffträger gekoppelt werden. Solche Polymere können Polyvinyl- pyrrolidon, Pyran-Copolymer, Polyhydroxypropylmethacrylamidphenol,The compounds of the invention as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled with soluble polymers as targeted drug carriers. Such polymers may include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol,
Polyhydroxyethylaspartamidphenol oder Polyethylenoxidpolylysin, substituiert mit Palmitoylresten, umfassen. Weiterhin können die Verbindungen an eine Klasse von biologisch abbaubaren Polymeren, die zur Erzielung einer kontrollierten Freisetzung eines Arzneistoffs geeignet sind, z.B. Polymilchsäure, Polyepsilon-Caprolacton, Polyhydroxybutter- säure, Polyorthoester, Polyacetale, Polydihydroxypyrane, Polycyano- acrylate und quervernetzte oder amphipatische Blockcopolymere von Hydrogelen, gekoppelt sein.Polyhydroxyethylaspartamidphenol or polyethylene oxide polylysine substituted with Palmitoylresten include. Furthermore, the compounds can be attached to a class of biodegradable polymers suitable for the controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyano-acrylates, and cross-linked or amphipathic block copolymers of hydrogels.
An die transdermale Verabreichung angepaßte pharmazeutischePharmaceutical adapted to transdermal administration
Formulierungen können als eigenständige Pflaster für längeren, engen Kontakt mit der Epidermis des Empfängers dargereicht werden. So kann beispielsweise der Wirkstoff aus dem Pflaster mittels lontophorese zugeführt werden, wie in Pharmaceutical Research, 3(6), 318 (1986) allgemein beschrieben. An die topische Verabreichung angepaßte pharmazeutische Verbindungen können als Salben, Cremes, Suspensionen, Lotionen, Pulver, Lösungen,Formulations may be presented as discrete plasters for prolonged, intimate contact with the epidermis of the recipient. For example, the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986). Pharmaceutical compounds adapted for topical administration may be used as ointments, creams, suspensions, lotions, powders, solutions,
Pasten, Gele, Sprays, Aerosole oder Öle formuliert sein.Be formulated pastes, gels, sprays, aerosols or oils.
Für Behandlungen des Auges oder anderer äußerer Gewebe, z.B. Mund und Haut, werden die Formulierungen vorzugsweise als topische Salbe oder Creme appliziert. Bei Formulierung zu einer Salbe kann der Wirkstoff entweder mit einer paraffinischen oder einer mit Wasser mischbaren Cremebasis eingesetzt werden. Alternativ kann der Wirkstoff zu einer Creme mit einer Öl-in-Wasser-Cremebasis oder einer Wasser-in-ÖI-Basis formuliert werden.For treatments of the eye or other external tissues, e.g. Mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated into an ointment, the active ingredient can be used with either a paraffinic or water miscible cream base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
Zu den an die topische Applikation am Auge angepaßten pharmazeutischen Formulierungen gehören Augentropfen, wobei der Wirkstoff in einem geeigneten Träger, insbesondere einem wäßrigen Lösungsmittel, gelöst oder suspendiert ist.The pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
An die topische Applikation im Mund angepaßte pharmazeutische Formulierungen umfassen Lutschtabletten, Pastillen und Mundspülmittel.Pharmaceutical formulations adapted for topical application in the mouth include lozenges, troches and mouthwashes.
An die rektale Verabreichung angepaßte pharmazeutische Formulierungen können in Form von Zäpfchen oder Einlaufen dargereicht werden.Pharmaceutical formulations adapted for rectal administration may be presented in the form of suppositories or enemas.
An die nasale Verabreichung angepaßte pharmazeutischePharmaceutical adapted to nasal administration
Formulierungen, in denen die Trägersubstanz ein Feststoff ist, enthalten ein grobes Pulver mit einer Teilchengröße beispielsweise im Bereich vonFormulations in which the vehicle is a solid include a coarse powder having a particle size, for example in the range of
20-500 Mikrometern, das in der Art und Weise, wie Schnupftabak aufgenommen wird, verabreicht wird, d.h. durch Schnellinhalation über die Nasenwege aus einem dicht an die Nase gehaltenen Behälter mit dem Pulver. Geeignete Formulierungen zur Verabreichung als Nasenspray oder Nasentropfen mit einer Flüssigkeit als Trägersubstanz umfassen Wirkstofflösungen in Wasser oder Öl.20-500 microns, which is administered in the manner in which snuff is taken, ie by rapid inhalation via the nasal passages from a container held close to the nose with the powder. Suitable formulations for administration as a nasal spray or Nasal drops containing a liquid carrier include drug solutions in water or oil.
An die Verabreichung durch Inhalation angepaßte pharmazeutischeFor administration by inhalation adapted pharmaceutical
Formulierungen umfassen feinpartikuläre Stäube oder Nebel, die mittels verschiedener Arten von unter Druck stehenden Dosierspendern mit Aerosolen, Verneblern oder Insufflatoren erzeugt werden können.Formulations include fine particulate dusts or mists that can be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.
An die vaginale Verabreichung angepaßte pharmazeutischePharmaceutical adapted to vaginal administration
Formulierungen können als Pessare, Tampons, Cremes, Gele, Pasten, Schäume oder Sprayformulierungen dargereicht werden.Formulations may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Zu den an die parenterale Verabreichung angepaßten pharmazeutischen Formulierungen gehören wäßrige und nichtwäßrige sterile Injektionslösungen, die Antioxidantien, Puffer, Bakteriostatika und Solute, durch die die Formulierung isotonisch mit dem Blut des zu behandelndenPharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the subject
Empfängers gemacht wird, enthalten; sowie wäßrige und nichtwäßrige sterile Suspensionen, die Suspensionsmittel und Verdicker enthalten können. Die Formulierungen können in Einzeldosis- oder Mehrfachdosisbehältern, z.B. versiegelten Ampullen und Fläschchen, dargereicht und in gefriergetrocknetem (lyophilisiertem) Zustand gelagert werden, so daß nur die Zugabe der sterilen Trägerflüssigkeit, z.B. Wasser für Injektionszwecke, unmittelbar vor Gebrauch erforderlich ist. Rezepturmäßig hergestellte Injektionslösungen und Suspensionen können aus sterilen Pulvern, Granulaten und Tabletten hergestellt werden.Recipient is included; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. The formulations may be administered in single or multiple dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use. Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
Es versteht sich, daß die Formulierungen neben den obigen besonders erwähnten Bestandteilen andere im Fachgebiet übliche Mittel mit Bezug auf die jeweilige Art der Formulierung enthalten können; so können beispielsweise für die orale Verabreichung geeignete FormulierungenIt will be understood that in addition to the above particularly mentioned ingredients, the formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration
Geschmacksstoffe enthalten. Eine therapeutisch wirksame Menge einer Verbindung der vorliegenden Erfindung hängt von einer Reihe von Faktoren ab, einschließlich z.B. dem Alter und Gewicht des Menschen oder Tiers, dem exakten Krankheitszustand, der der Behandlung bedarf, sowie seines Schweregrads, derFlavors contain. A therapeutically effective amount of a compound of the present invention will depend on a number of factors, including, for example, the age and weight of the human or animal, the exact disease condition requiring treatment, and its severity
Beschaffenheit der Formulierung sowie dem Verabreichungsweg, und wird letztendlich von dem behandelnden Arzt bzw. Tierarzt festgelegt. Jedoch liegt eine wirksame Menge einer erfindungsgemäßen Verbindung für die Behandlung im allgemeinen im Bereich von 0,1 bis 100 mg/kg Körper- gewicht des Empfängers (Säugers) pro Tag und besonders typisch im Bereich von 1 bis 10 mg/kg Körpergewicht pro Tag. Somit läge für einen 70 kg schweren erwachsenen Säuger die tatsächliche Menge pro Tag für gewöhnlich zwischen 70 und 700 mg, wobei diese Menge als Einzeldosis pro Tag oder üblicher in einer Reihe von Teildosen (wie z.B. zwei, drei, vier, fünf oder sechs) pro Tag gegeben werden kann, so daß die Gesamttagesdosis die gleiche ist. Eine wirksame Menge eines Salzes oder Solvats oder eines physiologisch funktionellen Derivats davon kann alsThe nature of the formulation and the route of administration, and is ultimately determined by the attending physician or veterinarian. However, an effective amount of a compound of the invention for treatment is generally in the range of 0.1 to 100 mg / kg of body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg of body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof may be mentioned as
Anteil der wirksamen Menge der erfindungsgemäßen Verbindung perse bestimmt werden. Es läßt sich annehmen, daß ähnliche Dosierungen für die Behandlung der anderen, obenerwähnten Krankheitszustände geeignet sind.Proportion of the effective amount of the compound according to the invention can be determined per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
Gegenstand der Erfindung sind ferner Arzneimittel enthaltend mindestens eine erfindungsgemäße Verbindung und/oder ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und mindestens einen weiteren Arzneimittelwirkstoff.The invention furthermore relates to medicaments comprising at least one compound according to the invention and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further active pharmaceutical ingredient.
Als weitere Arzneimittelwirkstoffe sind Chemotherapeutika bevorzugt, insbesondere solche, die Angiogenese hemmen und dadurch dasAs further active pharmaceutical ingredients chemotherapeutic agents are preferred, in particular those which inhibit angiogenesis and thereby the
Wachstum und die Verbreitung von Tumorzellen inhibieren; bevorzugt sind dabei VEGF-Rezeptorinhibitoren, beinhaltend Robozyme und Antisense, die auf VEGF-Rezeptoren gerichtet sind, sowie Angiostatin und Endostatin.Inhibit growth and proliferation of tumor cells; preferred are VEGF receptor inhibitors, including robozymes and antisense, which are directed to VEGF receptors, as well as angiostatin and endostatin.
Beispiele antineoplastischer Agenzien, die in Kombination mit den erfindungsgemäßen Verbindungen verwendet werden können, beinhalten im allgemeinen alkylierende Agenzien, Antimetaboliten; Epidophyllotoxin; ein antineoplastisches Enzym; einen Topoisomerase-Inhibitor;Examples of antineoplastic agents that can be used in combination with the compounds of the invention generally include alkylating agents, antimetabolites; Epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor;
Procarbazin; Mitoxantron oder Platin-Koordinationskomplexe.procarbazine; Mitoxantrone or platinum coordination complexes.
Antineoplastische Agenzien sind vorzugsweise ausgewählt aus den folgenden Klassen:Antineoplastic agents are preferably selected from the following classes:
Anthracycline, Vinca-Arzneistoffe, Mitomycine, Bleomycine, cytotoxische Nukleoside, Epothilone, Discodermolide, Pteridine, Diynene undAnthracyclines, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolides, pteridines, diynes, and
Podophyllotoxine.Podophyllotoxins.
Besonders bevorzugt sind in den genanten Klassen z.B. Carminomycin,Particularly preferred in the mentioned classes are e.g. caminomycin,
Daunorubicin, Aminopterin, Methotrexat, Methopterin, Dichlormethotrexat,Daunorubicin, aminopterin, methotrexate, methopterine, dichloromethotrexate,
Mitomycin C, Porfiromycin, 5-Fluoruracil, 6-Mercaptopurin, Gemcitabine,Mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine,
Cytosinarabinosid, Podophyllotoxin oder Podophyllotoxinderivate, wie z.B.Cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives, e.g.
Etoposide, Etoposide Phosphat oder Teniposide, Melphalan, Vinblastine, Vincristine, Leurosidine, Vindesine, Leurosine und Paclitaxel. Andere bevorzugte antineoplastische Agenzien sind ausgewählt aus der Gruppe Estramustine, Carboplatin, Cyclophosphamid, Bleomycin, Gemcitabine, Ifosamide, Melphalan, Hexamethylmelamin, Thiotepa, Cytarabin, Idatrexate, Trimetrexate, Dacarbazine, L-Asparaginase, Camptothecin, CPT-11, Topotecan, Arabinosyl-Cytosin, Bicalutamide, Flutamide, Leuprolide, Pyridobenzoindolderivate, Interferone und Interleukine.Etoposide, Etoposide Phosphate or Teniposide, Melphalan, Vinblastine, Vincristine, Leurosidine, Vindesine, Leurosine and Paclitaxel. Other preferred antineoplastic agents are selected from the group estramustins, carboplatin, cyclophosphamide, bleomycin, gemcitabine, ifosamide, melphalan, hexamethylmelamine, thiotepa, cytarabine, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, arabinosyl-cytosine , Bicalutamide, Flutamide, Leuprolide, Pyridobenzoindole derivatives, Interferons and Interleukins.
Gegenstand der Erfindung ist auch ein Set (Kit), bestehend aus getrennten Packungen vonThe invention is also a set (kit), consisting of separate packages of
(a) einer wirksamen Menge an einer erfindungsgemäßen Verbindung und/oder ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen(A) an effective amount of a compound of the invention and / or its pharmaceutically acceptable derivatives, solvates and Stereoisomers, including mixtures thereof in all
Verhältnissen, undRelationships, and
(b) einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs. 5(b) an effective amount of another drug. 5
Das Set enthält geeignete Behälter, wie Schachteln oder Kartons, individuelle Flaschen, Beutel oder Ampullen. Das Set kann z.B. separate Ampullen enthalten, in denen jeweils eine wirksame Menge an einerThe kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set may e.g. separate ampoules containing, in each case, an effective amount of a
10 erfindungsgemäßen Verbindung und/oder ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich derenCompound of the invention and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their
Mischungen in allen Verhältnissen, und einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs gelöstMixtures in all proportions, and dissolved in an effective amount of another drug
Λ C oder in lyophilisierter Form vorliegt.Λ C or in lyophilized form.
VERWENDUNGUSE
Die vorliegenden Verbindungen eignen sich als pharmazeutische Wirkstoffe für Säugetiere, insbesondere für den Menschen, bei der Behandlung von Krankheiten, bei denen HSP90 eine Rolle spielt.The present compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment of diseases in which HSP90 plays a role.
Gegenstand der Erfindung ist somit die Verwendung der erfindungs- 25 gemäßen Verbindungen, sowie ihrer pharmazeutisch verwendbarenThe invention thus relates to the use of the compounds according to the invention and their pharmaceutically usable compounds
Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, bei denen die Hemmung, Regulierung und/oder 30 Modulation von HSP90 eine Rolle spielt.Derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, for the manufacture of a medicament for the treatment of diseases involving the inhibition, regulation and / or modulation of HSP90.
Die vorliegende Erfindung umfasst die Verwendung der erfindungsgemäßen Verbindungen und/oder ihre physiologisch unbedenklichenThe present invention includes the use of the compounds of the invention and / or their physiologically acceptable
Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung von 35Salts and solvates for the manufacture of a medicament for the treatment of 35
Tumorerkrankungen, wie z.B. Fibrosarkom, Myxosarkom, Liposarkom, Chondrosarkom, osteogenem Sarkom, Chordom, Angiosarkom, Endo- theliosarkom, Lymphangiosarkom, Lymphangioendotheliosarkom, Synoviom, Mesotheliom, Ewing-Tumor, Leiosarkom, Rhabdomyosarkom,Tumor diseases such as fibrosarcoma, myxosarcoma, liposarcoma, Chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiosarcoma, rhabdomyosarcoma,
Kolonkarzinom, Pankreaskrebs, Brustkrebs, Ovarkrebs, Prostatakrebs,Colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
55
Plattenzellkarzinom, Basalzellkarzinom, Adenokarzinom, Schweißdrüsenkarzinom, Talgdrüsenkarzinom, Papillarkarzinom, Papillaradeno- karzinomen, Cystadenokarzinomen, Knochenmarkkarzinom, broncho- genem Karzinom, Nierenzellkarzinom, Hepatom, Gallengangkarzinom,Squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma,
10 Chorionkarzinom, Seminom, embryonalem Karzinom, Wilms-Tumor, Cervix-Krebs, Hodentumor, Lungenkarzinom, kleinzelligem Lungenkarzinom, Blasenkarzinom, Epithelkarzinom, Gliom, Astrocytom, Medulloblastom, Kraniopharyngiom, Ependymom, Pinealom, Hämangio-10 choriocarcinoma, seminoma, embryonic carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangio-
^c blastom, akustischem Neurom, Oligodendrogliom, Meningiom, Melanom, Neuroblastom, Retinoblastom, Leukämie, Lymphom, multiplem Myelom, Waldenströms Makroglobulinämie und Schwere-Kettenerkrankung; viralen Erkrankungen, wobei das virale Pathogen ausgewählt ist aus der^ c blastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia and severe chain disease; viral diseases, wherein the viral pathogen is selected from the
Gruppe, bestehend aus Hepatitis Typ A, Hepatitis Typ B, Hepatitis Typ C, 0Group consisting of hepatitis type A, type B hepatitis, type C hepatitis, 0
Influenza, Varicella, Adenovirus, Herpes-Simplex Typ I (HSV-I), HerpesInfluenza, varicella, adenovirus, herpes simplex type I (HSV-I), herpes
Simplex Typ Il (HSV-II), Rinderpest, Rhinovirus, Echovirus, Rotavirus, respiratorischem Synzytialvirus (RSV), Papillomvirus, Papovavirus, Cytomegalievirus, Echinovirus, Arbovirus, Huntavirus, Coxsackievirus,Simplex type II (HSV-II), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV), papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackievirus,
25 Mumpsvirus, Masernvirus, Röteinvirus, Poliovirus, menschliches Immunschwächevirus Typ I (HIV-I) und menschliches Immunschwächevirus Typ Il (HIV-II); zur Immunsuppression bei Transplantationen; entzündungsbedingten25 mumps virus, measles virus, rotten virus, poliovirus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II); for immunosuppression in transplantations; inflammation-related
3Q Erkrankungen, wie Rheumatoide Arthritis, Asthma, Sepsis, Multiple Sklerose, Typ 1 Diabetes, Lupus Erythematodes, Psoriasis und Inflammatory Bowel Disease; Zystische Fibrose; Erkrankungen im Zusammenhang mit Angiogenese wie z.B. diabetische Retinopathie, 3Q Diseases such as Rheumatoid Arthritis, Asthma, Sepsis, Multiple Sclerosis, Type 1 Diabetes, Lupus Erythematosus, Psoriasis and Inflammatory Bowel Disease; Cystic fibrosis; Diseases associated with angiogenesis such as diabetic retinopathy,
Hämangiome, Endometriose, Tumorangiogenese; infektiösenHemangiomas, endometriosis, tumor angiogenesis; infectious
3535
Erkrankungen; Autoimmunerkrankungen; Ischämie; Förderung derdiseases; Autoimmune diseases; ischemia; Promotion of
Nervenregeneration; fibrogenetischen Erkrankungen, wie z.B. Sklerodermie, Polymyositis, systemischer Lupus, Leberzirrhose, Keloidbildung, interstitielle Nephritis und pulmonare Fibrose;Nerve regeneration; fibrogenetic disorders, such as Scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis;
Die erfindungsgemäßen Verbindungen können insbesondere dasThe compounds according to the invention can in particular the
Wachstum von Krebs, Tumorzellen und Tumormetastasen hemmen und sind deshalb für die Tumortherapie geeignet.Growth of cancer, tumor cells and tumor metastases inhibit and are therefore suitable for tumor therapy.
Die vorliegende Erfindung umfasst weiterhin die Verwendung der erfindungsgemäßen Verbindungen und/oder ihre physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zum Schutz normaler Zellen gegen Toxizität, die durch Chemotherapie verursacht ist, sowie zur Behandlung von Krankheiten, wobei Proteinfehlfaltung oder Aggregation ein Hauptkausalfaktor ist, wie z.B. Skrapie, Creutzfeldt-Jakob-Krankheit, Huntington oder Alzheimer.The present invention further comprises the use of the compounds of the invention and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the protection of normal cells against toxicity caused by chemotherapy, as well as for the treatment of diseases, wherein protein misfolding or aggregation is a major causal factor, such as Scrapie, Creutzfeldt-Jakob Disease, Huntington or Alzheimer's.
Die Erfindung betrifft auch die Verwendung der erfindungsgemäßenThe invention also relates to the use of the invention
Verbindungen und/oder ihre physiologisch unbedenklichen Salze undCompounds and / or their physiologically acceptable salts and
Solvate zur Herstellung eines Arzneimittels zur Behandlung vonSolvates for the manufacture of a medicament for the treatment of
Krankheiten des Zentralnervensystems, von Herzkreislauferkrankungen und Kachexie.Diseases of the central nervous system, cardiovascular diseases and cachexia.
Die Erfindung betrifft in einer weiteren Ausführungsform auch die Verwendung der erfindungsgemäßen Verbindungen und/oder ihre physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur HSP90-Modulation, wobei die modulierte biologische HSP90-Aktivität eine Immunreaktion in einem Individuum, Proteintransport vom endoplasmatischen Retikulum, Genesung vom hypoxischen / anoxischen Stress, Genesung von Unterernährung, Genesung von Hitzestress, oder Kombinationen davon, hervorruft, und/oder wobei dieIn a further embodiment, the invention also relates to the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the production of a medicament for HSP90 modulation, wherein the modulated HSP90 biological activity comprises an immune reaction in an individual, endoplasmic reticulum protein transport, recovery from hypoxic / anoxic stress, recovery from malnutrition, recovery from heat stress, or combinations thereof, and / or wherein the
Störung eine Art Krebs ist, eine Infektionserkrankung, eine Störung, die mit einem gestörten Proteintransport vom endoplasmatischen Retikulum, einerDisorder is a type of cancer, an infectious disease that is associated with a disrupted protein transport from the endoplasmic reticulum, a
Störung, die mit Ischämie / Reperfusion einhergeht, oder Kombinationen davon, wobei die die mit Ischämie / Reperfusion einhergehende Störung eine Folge von Herzstillstand, Asystole und verzögerten ventrikulären Arrythmien, Herzoperation, kardiopulmonärer Bypass-Operation, Organtransplantation, Rückenmarksverletzung, Kopftrauma, Schlaganfall, thromboembolischem Schlaganfall, hämorrhagischem Schlaganfall, cerebralem Vasospasmus, Hypotonie, Hypoglykämie, Status epilepticus, einem epileptischem Anfall, Angst, Schizophrenie, einer neuro- degenerativen Störung, Alzheimer-Krankheit, Chorea Huntington, amyotropher lateraler Sklerose (ALS) oder Stress beim Neugeborenen ist.Disorder associated with ischemia / reperfusion, or combinations of which the ischemia / reperfusion-associated disorder is a consequence of cardiac arrest, asystole and delayed ventricular arrhythmias, heart surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord injury, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm, hypotension, hypoglycemia, Status epilepticus, epileptic seizure, anxiety, schizophrenia, neurodegenerative disorder, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), or neonatal stress.
Die Erfindung betrifft in einer weiteren Ausführungsform auch die Verwendung der erfindungsgemäßen Verbindungen und/oder ihre physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandeln von Ischämie als Folge von Herzstillstand, Asystole und verzögerten ventrikulären Arrythmien, Herzoperation, kardiopulmonärer Bypass-Operation, Organtransplantation, Rückenmarksverletzung, Kopftrauma, Schlaganfall, thromboembolischem Schlaganfall, hämorrhagischem Schlaganfall, cerebralem Vasospasmus, Hypotonie,In a further embodiment, the invention also relates to the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the preparation of a medicament for treating ischemia as a result of cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, Spinal cord injury, head trauma, stroke, thromboembolic stroke, haemorrhagic stroke, cerebral vasospasm, hypotension,
Hypoglykämie, Status epilepticus, einem epileptischem Anfall, Angst, Schizophrenie, einer neurodegenerativen Störung, Alzheimer-Krankheit, Chorea Huntington, amyotropher lateraler Sklerose (ALS) oder Stress beim Neugeborenen ist.Hypoglycemia, status epilepticus, an epileptic seizure, anxiety, schizophrenia, a neurodegenerative disorder, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), or neonatal stress.
Testverfahren zur Messung von HSP90 InhibitorenTest method for the measurement of HSP90 inhibitors
Die Bindung von Geldanamycin oder 17- Allylamino-17-demethoxy- geldanamycin (17AAG) und deren kompetitive Hemmung an HSP90 kann benutzt werden, um die inhibitorische Aktivität der erfindungsgemäßen Verbindungen zu bestimmen (Carreras et al. 2003, Chiosis et al. 2002).The binding of geldanamycin or 17-allylamino-17-demethoxy-geldanamycin (17AAG) and their competitive inhibition to HSP90 can be used to determine the inhibitory activity of the compounds of the invention (Carreras et al., 2003, Chiosis et al., 2002).
Im speziellen Fall wird ein Radioligand-Filterbindungstest verwendet. AlsIn the special case, a radioligand filter binding test is used. When
Radioligand wird dabei mit Tritium markiertes 17-Allylamino-geldanamycin, [3H]17AAG, verwendet. Dieser Filter-Bindungstest erlaubt eine gezielte Suche nach Inhibitoren, die mit der ATP-Bindestelle interferieren.Radioligand is thereby tritiated 17-allylamino-geldanamycin, [3H] 17AAG, used. This filter binding assay allows a targeted search for inhibitors that interfere with the ATP binding site.
Materialmaterial
Rekombinantes humanes HSP90α (E. coli exprimiert, 95% Reinheit); [3H]17AAG (17-Allylamino-geldanamycin, [allylamino-2,3-3H. Spezifische Aktivität: 1 ,11x1012 Bq/mmol (Moravek, MT-1717); HEPES Filterpuffer (50 mM HEPES, pH 7,0, 5mM MgCI2, BSA 0.01 %) Multiscreen-FB (1μm) Filterplatte (Millipore, MAFBNOB 50).Recombinant human HSP90α (expressing E. coli, 95% purity); [3H] 17AAG (17-allylamino-geldanamycin, [allylamino-2,3- 3 H. Specific activity: 1, 11x10 12 Bq / mmol (Moravek, MT-1717); HEPES filter buffer (50 mM HEPES, pH 7.0 , 5mM MgCl2, BSA 0.01%) Multiscreen FB (1μm) filter plate (Millipore, MAFBNOB 50).
Methodemethod
Die 96 well Mikrotiter-Filterplatten werden zunächst gewässert und mit 0,1% Polyethylenimin beschichtet.The 96 well microtiter filter plates are first watered and coated with 0.1% polyethyleneimine.
Der Test wird unter folgenden Bedingungen durchgeführt:The test is carried out under the following conditions:
Reaktionstemperatur 22 0CReaction temperature 22 ° C.
Reaktionszeit: 30 min., Schütteln bei 800 upmReaction time: 30 min., Shaking at 800 rpm
Testvolumen: 50 μlTest volume: 50 μl
Endkonzentrationen:final concentrations:
50 mM HEPES-HCI, pH7,0, 5 mM MgCI2, 0,01 % (w/v) BSA50 mM HEPES-HCl, pH 7.0, 5 mM MgCl 2, 0.01% (w / v) BSA
HSP90: 1 ,5 μg/assayHSP90: 1, 5 μg / assay
[3H]17AAG: 0,08 μM.[3H] 17AAG: 0.08 μM.
Am Ende der Reaktion wird der Überstand in der Filterplatte mit Hilfe eines Vakuum-Manifolds (Multiscreen Separation System, Millipore) abgesaugt und der Filter zweimal gewaschen. Die Filterplatten werden dann in einem Beta-counter (Microbeta, Wallac) mit Szintillator (Microscint 20, Packard) gemessen. Aus den „counts per minutes"-Werten wird „% der Kontrolle" ermittelt und daraus der IC-50 Wert einer Verbindung kalkuliert.At the end of the reaction, the supernatant in the filter plate is aspirated using a vacuum manifold (Millipore Multiscreen Separation System) and the filter washed twice. The filter plates are then measured in a beta counter (Microbeta, Wallac) with scintillator (Microscint 20, Packard). From the "counts per minutes" values "% of control" is determined and from this the IC-50 value of a connection is calculated.
Tabelle ITable I
HSP90-lnhibierung durch einige repräsentative erfindungsgemäße Verbindungen der Formel IHSP90 inhibition by some representative compounds of the formula I according to the invention
IC50: 10 nM - 1 μM = A 1 μM - 10 μM = B > 10 μM = CIC 50 : 10 nM - 1 μM = A 1 μM - 10 μM = B> 10 μM = C
Vor- und nachstehend sind alle Temperaturen in 0C angegeben. In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethylacetat oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, dampft ein und reinigt durch Chromatographie an Kieselgel und /oder durch Kristallisation. Rf-Werte an Kieselgel; Laufmittel: Ethylacetat/Methanol 9:1. LC-MS BedingungenAbove and below all temperatures are given in 0 C. In the following examples, "usual workup" means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracting with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Eluent: ethyl acetate / methanol 9: 1. LC-MS conditions
Hewlett Packard System der HP 1100 Serie mit den folgenden Merkmalen: lonenquelle: Elektrospray (positive mode); Scan: 100-1000 m/z;Hewlett Packard HP 1100 series system with the following features: Ion source: electrospray (positive mode); Scan: 100-1000 m / z;
Fragmentier-Spannung: 60 V; Gas-Temperatur: 3000C, DAD: 220 nm.Fragmentation voltage: 60 V; Gas temperature: 300 0 C, DAD: 220 nm.
Flussrate: 2.4 ml/Min. Der verwendete Splitter reduzierte nach dem DAD die Flussrate für das MS auf O,75ml/Min. Säule: Chromolith SpeedROD RP-18e 50-4.6Flow rate: 2.4 ml / min. The splitter used reduced the flow rate for the MS to O, 75 ml / min after the DAD. Column: Chromolith SpeedROD RP-18e 50-4.6
Lösungsmittel: LiChrosolv-Qualität der Fa. Merck KGaA Lösungsmittel A: H2O (0.01 % TFA) Lösungsmittel B: ACN (0.008% TFA)Solvent: LiChrosolv grade from Merck KGaA Solvent A: H2O (0.01% TFA) Solvent B: ACN (0.008% TFA)
Gradient:Gradient:
20% B → 100% B: 0 min bis 2.8 min 100% B: 2.8 min bis 3.3 min 100%B → 20%B: 3.3 min bis 4 min20% B → 100% B: 0 min to 2.8 min 100% B: 2.8 min to 3.3 min 100% B → 20% B: 3.3 min to 4 min
Gradient polar:Gradient polar:
5% B → 100% B: 0 min bis 3.0 min 100% B: 3.0 min bis 3.3 min5% B → 100% B: 0 min to 3.0 min 100% B: 3.0 min to 3.3 min
100%B → 20%B: 3.3 min bis 4 min100% B → 20% B: 3.3 min to 4 min
Die in den nachfolgenden Beispielen angegebenen Retentionszeiten RtThe retention times Rt
[min] und M+H+-Daten sind die Meßergebnisse der LC-MS-Messungen.[min] and M + H + data are the measurement results of the LC-MS measurements.
Beispiel 1example 1
Herstellung von 2-Amino-4-methylcarbamoyl-chinazolin ("A1") 1.1 Zu 37,1 ml Natriummethylat (30%ige Lösung in Methanol) gibt man 200 ml Methanol und fügt unter Euskühlung portionsweise 19,1 g Guanidiniumchlorid zu. Es wird 1 Stunde bei Raumtemperatur nachgerührt. Das ausgefallene Natriumchlorid wird abgetrennt. Das Filtrat wird eingeengt, das restliche Lösungsmittel wird entfernt und man erhält die freie Guanidiniumbase als Öl.Preparation of 2-amino-4-methylcarbamoyl-quinazoline ("A1") 1.1 To 37.1 ml of sodium methylate (30% solution in methanol) is added 200 ml of methanol and added under cooling with ice portionwise 19.1 g of guanidinium chloride. It is stirred for 1 hour at room temperature. The precipitated sodium chloride is separated off. The filtrate is concentrated, the residual solvent is removed and the free guanidinium base is obtained as an oil.
Zu der öligen Base gibt man 22,1 g (2-Amino-phenyl)-oxo-essigsäure,To the oily base is added 22.1 g of (2-amino-phenyl) -oxoacetic acid,
Kaliumsalz und rührt 4 Stunden bei 135°. Man kühlt ab, verdünnt mitPotassium salt and stirred for 4 hours at 135 °. Cool, dilute with
Wasser, säuert an und arbeitet wie üblich auf. Man erhält 8,8 g 2-Amino-4- carboxy-chinazolin;Water, acidifies and works up as usual. This gives 8.8 g of 2-amino-4-carboxy-quinazoline;
1H-NMR (500 MHz, DMSO-d6, TFA-di): δ [ppm] 8.18 (d, 1 H), 8.05 (dd, 1H), 1 H-NMR (500 MHz, DMSO-d 6 , TFA-di): δ [ppm] 8.18 (d, 1H), 8.05 (dd, 1H),
7.74 (d, 1 H), 7.59 (dd, 1 H).7.74 (d, 1H), 7.59 (dd, 1H).
1.2 100 mg 2-Amino-4-carboxy-chinazolin und 261 ,6 mg Ethyl-2-ethoxy- 1 ,2-dihydrochinolin-1-carboxylat werden in 5 ml Acetonitril suspendiert und mit 146,6 μl Triethylamin versetzt. Man gibt 53,6 mg Methylammoniumchlorid zu und rührt 16 Stunden bei 80° (Badtemperatur). Man kühlt ab, entfernt das Lösungsmittel und reinigt mittels RP-Flashchromatographie (Isco Compamion®);1.2 100 mg of 2-amino-4-carboxy-quinazoline and 261, 6 mg of ethyl 2-ethoxy-1, 2-dihydroquinoline-1-carboxylate are suspended in 5 ml of acetonitrile and treated with 146.6 ul of triethylamine. Are added 53.6 mg of methyl ammonium chloride and stirred for 16 hours at 80 ° (bath temperature). The solvent mixture is cooled, removed and purified by RP-flash chromatography (Isco Compamion ®);
Ausbeute: 39,0 mg "A1";Yield: 39.0 mg "A1";
1H-NMR (500 MHz, DMSO-d6, TFA-di): δ [ppm] 8.31 (d, 1 H), 8.04 (dd, 1 H), 1 H-NMR (500 MHz, DMSO-d 6 , TFA-di): δ [ppm] 8.31 (d, 1 H), 8.04 (dd, 1 H),
7.75 (d, 1 H)1 7.59 (dd, 1 H), 2.93 (s, 3H).7.75 (d, 1H) 1 7.59 (dd, 1H), 2.93 (s, 3H).
Analog werden die nachstehenden Verbindungen erhaltenAnalogously, the following compounds are obtained
"A19" 2-Amino-4-propargyl-methyl- 1 ,105 241 ,27 carbamoyl-chinazolin "A19" 2-Amino-4-propargyl-methyl-1,105,241,27-carbamoyl-quinazoline
"A20" 2-Amino-4-[(2-methoxyethyl)-methyl- 1 ,016 261 ,3 carbamoyl]-chinazolin"A20" 2-Amino-4 - [(2-methoxyethyl) -methyl-1,116,261,3-carbamoyl] -quinazoline
"A22" 2-Amino-4-[(4-methylsulfonylamino- 1 ,247 386,45 benzyl))-methyl-carbamoyl]-chinazolin"A22" 2-Amino-4 - [(4-methylsulfonylamino-1,27,36,45benzyl)) methylcarbamoyl] quinazoline
"A23" 2-Amino-4-[(3-methylsulfonylamino- 1 ,287 386,45 benzyl))-methyl-carbamoyl]-chinazolin"A23" 2-Amino-4 - [(3-methylsulfonylamino-1, 287.386.45 benzyl)) methyl-carbamoyl] quinazoline
"A24" 2-Amino-4-[(benzo[1 ,4]dioxan-6-yl)- 1 ,493 351 ,38 methyl-carbamoyl]-chinazolin"A24" 2-Amino-4 - [(benzo [1,4] dioxan-6-yl) -1,493,301,38-methylcarbamoyl] quinazoline
"A25" 2-Amino-4-[(4-[1 ,2,4]triazol-1- 1 ,247 374,42 ylmethyl-benzyl)]-methyl-carbamoyl]- chinazolin"A25" 2-Amino-4 - [(4- [1,2,4] triazole-1,1,247,374,42-ylmethyl-benzyl)] -methyl-carbamoyl] -quinazoline
Beispiel 2Example 2
Herstellung von 2-Amino-4-(3-hydroxy-pyrrolidin-1-ylcarbonyl)-chinazolin ("A17")Preparation of 2-amino-4- (3-hydroxy-pyrrolidin-1-ylcarbonyl) quinazoline ("A17")
Zu einer Lösung von 100 mg 2-Amino-4-carboxy-chinazolin in 2 ml DMF gibt man 68,76 μl Isobutylchloroformiat und 63,93 μl 4-Methylmorpholin. Man rührt 30 Minuten bei Raumtemperatur, gibt 50,66 mg 3-Hydroxy- pyrrolidin dazu und rührt 30 Minuten nach. Nach üblicher Aufarbeitung erhält man 55,7 mg "A17"; Rt 0,797; M+H+ 259,28.To a solution of 100 mg of 2-amino-4-carboxy-quinazoline in 2 ml of DMF are added 68.76 μl of isobutyl chloroformate and 63.93 μl of 4-methylmorpholine. The mixture is stirred at room temperature for 30 minutes, 50.66 mg of 3-hydroxy-pyrrolidine are added thereto and stirring is continued for 30 minutes. After usual work-up, 55.7 mg of "A17" are obtained; Rt 0.797; M + H + 259.28.
Analog werden die nachstehenden Verbindungen erhalten Analogously, the following compounds are obtained
Beispiel 3Example 3
Herstellung von 2-Amino-6-methyl-4-(5-methoxy-1 ,3-dihydro-isoindol-2-yl- carbonyl)-chinazolin ("A92")Preparation of 2-amino-6-methyl-4- (5-methoxy-1,3-dihydroisoindol-2-ylcarbonyl) quinazoline ("A92")
Eine Mischung von 56,6 mg "A91", 11 μl lodmethan und 48,8 mg Kaliumcarbonat in 2 ml Aceton wird 16 Stunden gerührt. Das Lösungsmittel wird entfernt, der Rückstand in 1 DMSO gelöst und über HPLC gereinigt, man erhält 19 mg "A92"; Rt 1 ,590; M+H+ 335,38.A mixture of 56.6 mg of "A91", 11 μl of iodomethane and 48.8 mg of potassium carbonate in 2 ml of acetone is stirred for 16 hours. The solvent is removed, the residue is dissolved in 1 DMSO and purified by HPLC to give 19 mg "A92"; Rt 1, 590; M + H + 335.38.
Analog erhält manAnalog obtained
2-Amino-6-methyl-4-(5-ethoxy-1 ,3-dihydro-isoindol-2-yl-carbonyl)- chinazolin ("A93"); Rt 1 ,772; M+H+ 349,41 ;2-amino-6-methyl-4- (5-ethoxy-1,3-dihydroisoindol-2-ylcarbonyl) quinazoline ("A93"); Rt 1, 772; M + H + 349.41;
2-Amino-6-methyl-4-(5-isopropoxy-1 ,3-dihydro-isoindol-2-yl- carbonyl)-chinazolin (MA94"); Rt 1 ,876; M+H+ 363,43;2-amino-6-methyl-4- (5-isopropoxy-1,3-dihydroisoindol-2-ylcarbonyl) quinazoline ( M A94 "); Rt 1, 876; M + H + 363.43;
Beispiel 4Example 4
Herstellung von 2-Amino-6-iod-4-(1 ,3-dihydro-isoindol-2-yl-carbonyl)- chinazolin ("A130M) 4.1 5-lodo-2,3-dioxo-2,3-dihydro-indol-1 -carbonsäure-tert.-butylesterPreparation of 2-amino-6-iodo-4- (1,3-dihydro-isoindol-2-yl-carbonyl) -quinazoline ("A130 M ) 4.1 tert-Butyl 5-iodo-2,3-dioxo-2,3-dihydro-indole-1-carboxylate
50 g 5-lodo-1 H-indol-2,3-dion werden in 500 ml THF gelöst, auf 100C abgekühlt und mit 43,97 g Di-tert.-butyldicarbonat versetzt. Es wird bei 23°C 16 h gerührt und das Gemisch anschließend im Vakuum zur Trockne eingeengt. Man nimmt in Petrolether und THF auf und kristallisiert bei -20 0C. Der so erhaltene gelbe Feststoff wird filtriert und bei 300C im Trockenschrank getrocknet. Ausbeute: 62,41 g 5-lodo-2,3-dioxo-2,3- dihydro-indol-1-carbonsäure-tert.-butyl ester; Retentionszeit LC-MS: 2,113 min.50 g of 5-iodo-1H-indole-2,3-dione are dissolved in 500 ml of THF, cooled to 10 0 C and treated with 43.97 g of di-tert-butyl dicarbonate. The mixture is stirred at 23 ° C for 16 h and then the mixture concentrated in vacuo to dryness. It is taken up in petroleum ether and THF and crystallized at -20 0 C. The resulting yellow solid is filtered and dried at 30 0 C in a drying oven. Yield: 62.41 g of tert-butyl 5-iodo-2,3-dioxo-2,3-dihydro-indole-1-carboxylate; Retention time LC-MS: 2.113 min.
4.2 {2-[2-(1 ,3-Dihydro-isoindol-2-yl)-2-oxo-acetyl]-4-iodo-phenyl}- carbaminsäure-tert.-butylester4.2. {2- [2- (1,3-Dihydro-isoindol-2-yl) -2-oxo-acetyl] -4-iodo-phenyl} -carbamic acid tert -butyl ester
62,41 g 5-lodo-2,3-dioxo-2,3-dihydro-indol-1 -carbonsäure-tert.-butylester werden in getrocknetem THF gelöst und mit 18,98 ml Isoindolin versetzt. Es wird 30 min bei 25°C gerührt, im Vakuum zur Trockne eingeengt und der Rückstand mit Petrolether verrieben, Filtration liefert 82,3 g {2-[2-(1 ,3- Dihydro-isoindol-2-yl)-2-oxo-acetyl]-4-iodo-phenyl}-carbaminsäure-tert.- butylester (beiger Feststoff); Retentionszeit LC-MS: 2,63 min; 1H NMR (500 MHz, DMSO/TFA): δ [ppm] 8.014 (d, 1H), 7.962 (dd, 1 H)1 7.913 (d, 1H), 7.391 (d, 1H), 7.326-7.292 (m, 3H), 4.901 (s, 2H), 4.872 (s, 2H), 1.398 (s, 9H).62.41 g of tert-butyl 5-iodo-2,3-dioxo-2,3-dihydro-indole-1-carboxylate are dissolved in dried THF and admixed with 18.98 ml of isoindoline. It is stirred for 30 min at 25 ° C, concentrated to dryness in vacuo and the residue triturated with petroleum ether, filtration provides 82.3 g of {2- [2- (1, 3-dihydro-isoindol-2-yl) -2- oxo-acetyl] -4-iodo-phenyl} -carbamic acid tert-butyl ester (beige solid); Retention time LC-MS: 2.63 min; 1 H NMR (500 MHz, DMSO / TFA): δ [ppm] 8.014 (d, 1H), 7.962 (dd, 1H) 1 7.913 (d, 1H), 7.391 (d, 1H), 7.326-7.292 (m , 3H), 4.901 (s, 2H), 4.872 (s, 2H), 1.398 (s, 9H).
4.34.3
24,50 g {2-[2-(1 ,3-Dihydro-isoindol-2-yl)-2-oxo-acetyl]-4-iodo-phenyl}- carbaminsäure-tert.-butylester werden in 500 ml Acetonitril unter Argon gelöst. Man gibt 0,756 g Cäsiumfluorid dazu und tropft über 5 min 16,887 ml Bis(trimethylsilyl)carbodiimid zu der Lösung. Es wird 15 min bei Raumtemperatur gerührt und mit 400 ml Dichlormethan versetzt. Nach Zugabe von 400 ml Salzsäure (1 N) fällt das Produkt als weißer Feststoff aus. Ausbeute: 14 g "A130"; Retentionszeit LC-MS: 1 ,655 min;24.50 g of {2- [2- (1, 3-dihydro-isoindol-2-yl) -2-oxo-acetyl] -4-iodo-phenyl} - carbamic acid tert-butyl ester in 500 ml of acetonitrile Argon solved. Add 0.756 g of cesium fluoride and dropwise over 5 min 16.887 ml of bis (trimethylsilyl) carbodiimide to the solution. It is stirred for 15 min at room temperature and treated with 400 ml of dichloromethane. After addition of 400 ml of hydrochloric acid (1 N), the product precipitates out as a white solid. Yield: 14 g "A130"; Retention time LC-MS: 1.655 min;
1H NMR (500 MHz, DMSO) δ [ppm] 8.143 (d, 1 H), 7.957 (dd, 1 H), 7.451 (d, 1 H), 7.361-7.256 (m, 4H), 7.213 (s, 2H), 4.993 (s, 2H), 4.745 (s, 2H). 1 H NMR (500 MHz, DMSO) δ [ppm] 8,143 (d, 1H), 7,957 (dd, 1H), 7,451 (d, 1H), 7,361-7,256 (m, 4H), 7,213 (s, 2H), 4,993 (s, 2H), 4,745 (s, 2H).
Beispiel 5Example 5
Herstellung von 2-Amino-6-phenyl-4-(1 ,3-dihydro-isoindol-2-yl-carbonyl)- chinazolin ("A131") [Suzuki-Kopplung]Preparation of 2-amino-6-phenyl-4- (1,3-dihydroisoindol-2-ylcarbonyl) quinazoline ("A131") [Suzuki Coupling]
Eine Mischung von 160 mg "A130", 56,24 mg Benzolboronsäure, 2 ml Ethylenglycoldimethylether, 22,21 mg Tetrakis(triphenylphosphin)- palladium(O), 106,25 mg Kaliumcarbonat und 50 μl Wasser wird unter Argonatmosphäre 30 Minuten bei 120° in der Mikrowelle bestrahlt. Man gießt auf Wasser und extrahiert mit Dichlormethan. Man trocknet und entfernt das Lösungsmittel. Man löst in 1 ml DMSO und chromatographiert mittels HPLC. Man erhält 10 mg "A131";A mixture of 160 mg of "A130", 56.24 mg of benzoic boronic acid, 2 ml of ethylene glycol dimethyl ether, 22.21 mg of tetrakis (triphenylphosphine) palladium (O), 106.25 mg of potassium carbonate and 50 .mu.l of water is heated under an argon atmosphere at 120.degree irradiated in the microwave. you Pour on water and extract with dichloromethane. It is dried and the solvent is removed. Dissolve in 1 ml of DMSO and chromatograph by HPLC. 10 mg of "A131" are obtained;
1H-NMR (500 MHz1 DMSO-d6): δ [ppm] 8.080 (dd, 1 H), 7.984 (d, 1H), 7.703-7.260 (m, 10H), 7.125 (s, 2H), 5.021 (s, 2H), 4.752 (s, 2H). 1 H-NMR (500 MHz 1 DMSO-d 6 ): δ [ppm] 8,080 (dd, 1H), 7,984 (d, 1H), 7,703-7,260 (m, 10H), 7,125 (s, 2H), 5,021 (s, 2H), 4.752 (s, 2H).
Analog werden die nachstehenden Verbindungen erhaltenAnalogously, the following compounds are obtained
Beispiel 6Example 6
Herstellung von 2-Amino-6-brom-4-(1 ,3-dihydro-isoindol-2-yl-carbonyl)- chinazolin ("A137")Preparation of 2-amino-6-bromo-4- (1,3-dihydro-isoindol-2-yl-carbonyl) -quinazoline ("A137")
Eine Lösung von 800 mg 1-(2-BOC-Amino-5-brom-phenyl)-2-(1 ,3-dihydro- isoindol-2-yl)-ethan-1 ,2-dion in 5 ml trockenem THF wird mit 1 ,09 g Cäsiumfluorid versetzt. Dann wird eine Lösung von 0,813 ml N1N1- Bis(trimethylsilyl)carbodiimid in 1 ml THF innerhalb von 10 Minuten zugetropft und 1 Stunde unter Argonatmosphäre bei Raumtemperatur gerührt. Man gießt auf Wasser und extrahiert mit Dichlormethan. Man trocknet und entfernt das Lösungsmittel. Man erhält 302 mg "A137".A solution of 800 mg of 1- (2-BOC-amino-5-bromo-phenyl) -2- (1,3-dihydro-isoindol-2-yl) -ethane-1,2-dione in 5 ml of dry THF is added admixed with 1.10 g of cesium fluoride. Then, a solution of 0.813 ml of N 1 N 1 - bis (trimethylsilyl) carbodiimide in 1 ml of THF is added dropwise within 10 minutes and stirred for 1 hour under an argon atmosphere at room temperature. It is poured into water and extracted with dichloromethane. It is dried and the solvent is removed. This gives 302 mg of "A137".
Analog werden die nachstehenden Verbindungen erhalten Analogously, the following compounds are obtained
Beispiel 7Example 7
Herstellung von 2-Amino-6-(butyl-methyl-carbamoyl)-4-diethylcarbamoyl- chinazolin ("A139")Preparation of 2-amino-6- (butylmethylcarbamoyl) -4-diethylcarbamoylquinazoline ("A139")
Im Autoklaven werden bei 30 bar und 130° umgesetzt:In an autoclave are reacted at 30 bar and 130 °:
100 mg 2-Amino-6-brom-4-diethylcarbamoyl-chinazolin, 30 ml 1 ,4-Dioxan,100 mg of 2-amino-6-bromo-4-diethylcarbamoyl-quinazoline, 30 ml of 1,4-dioxane,
7 ml Kohlenmonoxid, 10 mg (1 ,1'-Bis(diphenylphosphino)-ferrocen)- dichloropalladium(ll), 50 mg N,N,N',N'-tetramethylethylendiamin und 80 mg7 ml of carbon monoxide, 10 mg of (1, 1'-bis (diphenylphosphino) ferrocene) -dichloropalladium (II), 50 mg of N, N, N ', N'-tetramethylethylenediamine and 80 mg
N-Methylbutylamin. Nach der Umsetzung wird das Lösungsmittel entfernt und der Rückstand RP-flashchromatographiert (Isco Companion®), anschließend lyophilisiert. Man erhält 42,4 mg "A139"N-methylbutylamine. After the reaction, the solvent is removed and the residue RP-flash chromatographed (Isco Companion ®), then lyophilized. This gives 42.4 mg "A139"
Analog werden die nachstehenden Verbindungen erhaltenAnalogously, the following compounds are obtained
Beispiel 8Example 8
Herstellung von 2-Amino-6-((E)-2-methoxycarbonyl-vinyl)-4-(1 ,3-dihydro- isoindol-2-yl-carbonyl)-chinazolin ("A142")Preparation of 2-amino-6 - ((E) -2-methoxycarbonyl-vinyl) -4- (1,3-dihydro-isoindol-2-yl-carbonyl) -quinazoline ("A142")
Eine Mischung von 562 mg "A130", 122,3 μl Methylacrylat, 374,3 μlA mixture of 562 mg "A130", 122.3 μl of methyl acrylate, 374.3 μl
Triethylamin, 15,15 mg Palladium(ll)acetat, 20,55 mg Tris-o-toylamin und 4 ml Acetonitril wird unter Argonatmosphäre 30 Minuten bei 120° in der Mikrowelle bestrahlt. Man gießt auf Wasser und extrahiert mit Dichlormethan. Man trocknet und entfernt das Lösungsmittel. Der Rückstand wird in wenig Acetonitril aufgenommen. Das Produkt fällt unter Ultraschallbestrahlung aus. Man erhält 196,5 mg "A142"Triethylamine, 15.15 mg of palladium (II) acetate, 20.55 mg of tris-o-toylamine and 4 ml of acetonitrile is irradiated under argon atmosphere for 30 minutes at 120 ° in the microwave. It is poured into water and extracted with dichloromethane. It is dried and the solvent is removed. The residue is taken up in a little acetonitrile. The product precipitates under ultrasound irradiation. This gives 196.5 mg "A142"
Durch Hydrierung in THF mit Palladium/Aktivkohle erhält man aus "A142" die Verbindung 2-Amino-6-(2-methoxycarbonyl-ethyl)-4-(1 ,3-dihydro- isoindol-2-yl-carbonyl)-chinazolin ("A143"); Rt 1 ,615; M+H+ 377,42; und daraus durch Esterhydrolyse die Verbindung 2-Amino-6-(2-carboxy-ethyl)-4-(1 ,3-dihydro-isoindol-2-yl- carbonyl)-chinazolin ("A143a"); Rt 1 ,399; M+H+ 363,39.Hydrogenation in THF with palladium / activated carbon gives the compound 2-amino-6- (2-methoxycarbonyl-ethyl) -4- (1,3-dihydro-isoindol-2-yl-carbonyl) quinazoline from "A142" ( "A143"); Rt 1, 615; M + H + 377.42; and from ester hydrolysis, the compound 2-amino-6- (2-carboxy-ethyl) -4- (1,3-dihydro-isoindol-2-ylcarbonyl) quinazoline ("A143a"); Rt 1, 399; M + H + 363.39.
Durch Esterhydrolyse erhält man unter Standardbedingungen aus "A142" die Verbindung (E)-3-[2-Amino-4-(1 ,3-dihydro-isoindol-2-carbonyl)- chinazolin-6-yl]-acrylsäure ("A142a"); Rt (polar) 1 ,499; M+H+ 361 ,37Ester hydrolysis gives the compound (E) -3- [2-amino-4- (1,3-dihydro-isoindole-2-carbonyl) -quinazolin-6-yl] -acrylic acid under standard conditions from "A142"("A142a"); Rt (polar) 1, 499; M + H + 361, 37
Analog werden die nachstehenden Verbindungen erhalten Analogously, the following compounds are obtained
Beispiel 9Example 9
Herstellung von 2-Amino-6-(3-trimethylsilanyl-prop-1-inyl)-4-(1 ,3-dihydro- isoindol-2-yl-carbonyl)-chinazolin ("A146")Preparation of 2-amino-6- (3-trimethylsilanyl-prop-1-ynyl) -4- (1,3-dihydro-isoindol-2-yl-carbonyl) -quinazoline ("A146")
Eien Mischung von 100 mg "A130", 42,98 μl Trimethyl-prop-2-inyl-silan, 3,37 mg Bis(triphenylphosphin)-palladium(ll)-chlorid, 1 ,83 mg Kupfer(l)iodid, 0,16 ml Triethylamin und 0,5 ml DMF wird unter Argonatmosphäre 30 Minuten bei Raumtemperatur gerührt. Die Lösung wird danach unter vermindertem Druck bis zur Trockne eingedampft. Man gibt 1 ml Acetonitril dazu und chromatographiert mittels präparativer HPLC. Man erhält 18 mg "A146"; Rt 2,441 ; M+H+ 401 ,56.A mixture of 100 mg "A130", 42.98 μl of trimethyl-prop-2-ynylsilane, 3.37 mg of bis (triphenylphosphine) -palladium (II) chloride, 1.83 mg of copper (I) iodide, 0 , 16 ml of triethylamine and 0.5 ml of DMF is stirred under argon atmosphere for 30 minutes at room temperature. The solution is then evaporated to dryness under reduced pressure. Add 1 ml of acetonitrile and chromatograph by preparative HPLC. This gives 18 mg "A146"; Rt 2,441; M + H + 401, 56.
Die Abspaltung der Trimethylsilylgruppe erfolgt durch Rühren von 15 mg "A146" in 2 ml THF und 4,47 μl KOH (47%). Man gießt in Wasser und extrahiert mit Ethylacetat. Nach üblicher Aufarbeitung erhält man 12 mg 2-Amino-6-(prop-1-inyl)-4-(1 ,3-dihydro-isoindol-2-yl-carbonyl)-chinazolinThe cleavage of the trimethylsilyl group is carried out by stirring 15 mg of "A146" in 2 ml of THF and 4.47 μl of KOH (47%). It is poured into water and extracted with ethyl acetate. After usual workup, 12 mg of 2-amino-6- (prop-1-ynyl) -4- (1, 3-dihydro-isoindol-2-yl-carbonyl) quinazoline
("A147")( "A147")
Rt 1 ,873; M+H+ 329,37. Analog werden die nachstehenden Verbindungen erhalten Rt 1, 873; M + H + 329.37. Analogously, the following compounds are obtained
Analog Beispiel 1 oder Beispiel 4 werden die nachstehenden Verbindungen der Formel Ia, Ib, Ic und Id erhalten (Tabellen 1 - 4)Analogously to Example 1 or Example 4, the following compounds of the formula Ia, Ib, Ic and Id are obtained (Tables 1 to 4)
Tabelle 1Table 1
Verbindungen der Formel IaCompounds of the formula Ia
Tabelle 2Table 2
Verbindungen der Formel IbCompounds of the formula Ib
Tabelle 3Table 3
Verbindungen der Formel IcCompounds of the formula Ic
4846 4846
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Tabelle 4Table 4
Verbindungen der Formel IdCompounds of the formula Id
Beispiel 10Example 10
Analog Beispiel 5 werden die nachstehenden Verbindungen erhaltenAnalogously to Example 5, the following compounds are obtained
"A918" 2-Amino-6-(2-cyan-phenyl)-4-(1 ,3- 1 ,885 392,43 dihydro-isoindol-2-yl-carbonyl)-chinazolin "A918" 2-Amino-6- (2-cyanophenyl) -4- (1,3-bis, 885,392,43-dihydro-isoindol-2-yl-carbonyl) quinazoline
"A919" 2-Amino-6-(3-cyanmethyl-phenyl)-4-(1 ,3- 1 ,680 406,46 dihydro-isoindol-2-yl-carbonyl)-chinazolin"A919" 2-Amino-6- (3-cyanomethylphenyl) -4- (1,3- 1,680,406,46 dihydro-isoindol-2-yl-carbonyl) quinazoline
1H NMR (500 MHz, DMSO/TFA) δ [ppm] 8.343 (dd, 1H), 8.248 (d, 1H), 7.857 (d, 1H), 7.680 (m, 2H), 7.515 (m, 1H), 7.426 (t, 2H), 7.323 (t, 1H), 7.277 (t, 1 H), 7.224 (d, 1 H), 5.046 (s, 2H), 4.854 (s, 2H), 4.074 (s, 2H) 1 H NMR (500 MHz, DMSO / TFA) δ [ppm] 8.343 (dd, 1H), 8.248 (d, 1H), 7.857 (d, 1H), 7.680 (m, 2H), 7.515 (m, 1H), 7,426 (t, 2H), 7,323 (t, 1H), 7,277 (t, 1H), 7,224 (d, 1H), 5,046 (s, 2H), 4,854 (s, 2H), 4,074 (s, 2H)
"A921" 2-Amino-6-(benzofuran-2-yl)-4-(1 ,3- 2,236 407,44 dihydro-isoindol-2-yl-carbonyl)-chinazolin"A921" 2-Amino-6- (benzofuran-2-yl) -4- (1,3,2,236,407.44 dihydro-isoindol-2-yl-carbonyl) quinazoline
1H NMR (500 MHz, DMSO/TFA) δ [ppm] 8.343 (dd, 1H), 8.248 (d, 1 H), 7.680 (m, 2H), 7.515 (m, 1H), 7.426 (t, 2H), 7.323 (t, 1H), 7.277 (t, 1H), 7.224 (d, 1 H), 5.046 (s, 2H), 4.854 (s, 2H), 4.074 (s, 2H) 1 H NMR (500 MHz, DMSO / TFA) δ [ppm] 8,343 (dd, 1H), 8,248 (d, 1H), 7,680 (m, 2H), 7,515 (m, 1H), 7,426 (t, 2H) , 7.323 (t, 1H), 7.277 (t, 1H), 7.224 (d, 1H), 5.046 (s, 2H), 4.854 (s, 2H), 4.074 (s, 2H)
"A922" 2-Amino-6-(pyridin-4-yl)-4-(1,3-dihydro- 1 ,288 368,41 isoindol-2-yl-carbonyl)-chinazolin"A922" 2-Amino-6- (pyridin-4-yl) -4- (1,3-dihydro-1,288,368,41-isoindol-2-yl-carbonyl) quinazoline
1H NMR (500 MHz, DMSO/TFA) δ [ppm] 9.014 (d, 2H), 8.580 (d, 2H), 8.506 (d, 2H), 7.910 (d, 1 H), 7.463 (d, 1 H), 7.358-7.283 (m, 2H), 7.241 (d, 1 H), 5.062 (s, 2H), 4.860 (s, 2H) 1 H NMR (500 MHz, DMSO / TFA) δ [ppm] 9.014 (d, 2H), 8.580 (d, 2H), 8.506 (d, 2H), 7.910 (d, 1H), 7.463 (d, 1H ), 7,358-7,283 (m, 2H), 7,241 (d, 1H), 5,062 (s, 2H), 4,860 (s, 2H)
"A923" 2-Amino-6-(pyridin-3-yl)-4-(1 ,3-dihydro- 1 ,315 368,41 isoindol-2-yl-carbonyl)-chinazolin "A923" 2-Amino-6- (pyridin-3-yl) -4- (1,3-dihydro-1,315,68,41-isoindol-2-yl-carbonyl) quinazoline
Beispiel 11Example 11
Herstellung von 2-Amino-6-(2-piperazin-1-ylmethyl-phenyl)-4-(1 ,3-dihydro- isoindol-2-yl-carbonyl)-chinazolin ("A926") [Reduktive Aminierung]Preparation of 2-amino-6- (2-piperazin-1-ylmethylphenyl) -4- (1,3-dihydroisoindol-2-ylcarbonyl) quinazoline ("A926") [Reductive Amination]
In einem Reaktionsgläschen, versehen mit einem Magnetrührer, wird der Aldehyd "A96911 in 1 ml 1 ,2-Dichlorethan und 1 ml THF gelöst, mit Piperazin versetzt, Eisessig zugegeben und 0,5 h bei RT gerührt. Dann wird Natriumtriacetoxyborhydrid zugegeben und weitere 3h bei RT gerührt. Anschließend wird das Reaktionsgemisch in Wasser gegossen und mit CH2CI2 extrahiert, die vereinigten organischen Phasen getrocknet, filtriert und das Lösungsmittel wird entfernt. Der Rückstand wird in 1 ml DMSO gelöst und mittels präp. HPLC (Fa. Agilent) chromatographiert. Die erhaltenen sauberen Frakionen werden anschließend eingeengt und gefriergetrocknet. Man erhält "A926", Rt [min] HPLC Methode polar: 1 ,463; M+H+ 465,57.In a reaction glass, equipped with a magnetic stirrer, the aldehyde "A969 11 is dissolved in 1 ml of 1,2-dichloroethane and 1 ml of THF, treated with piperazine, glacial acetic acid is added and the mixture is stirred for 0.5 h at RT, then sodium triacetoxyborohydride is added and more The reaction mixture is stirred for 3 h at RT, then the reaction mixture is poured into water and extracted with CH 2 Cl 2 , the combined organic phases are dried, filtered and the solvent is removed The residue is dissolved in 1 ml DMSO and purified by prep HPLC (Agilent The resulting clean fractions are then concentrated and freeze-dried to give "A926", Rt [min] HPLC method polar: 1, 463; M + H + 465.57.
Analog werden die nachstehenden Verbindungen erhalten Analogously, the following compounds are obtained
Beispiel 12Example 12
Durch Reduktion erhält man aus "A918" unter Standardbedingungen die Verbindung "A936", Rt [min] HPLC Methode polar: 1 ,435; M+H+ 396,47;Reduction is obtained from "A918" under standard conditions, the compound "A936", Rt [min] HPLC method polar: 1, 435; M + H + 396.47;
1H NMR (500 MHz, DMSO/TFA) δ [ppm] 8.032 (m, 2H), 7.846 (d, 1 H), 7.526 (m, 1 H), 7.436 (m, 2H), 7.380 (m, 1H), 7.329 (m, 1H), 7.274 (m, 2H), 7.196 (m, 1 H)1 4.980 (s, 2H), 4.816 (s, 2H), 3,939 (m, 2H). 1 H NMR (500 MHz, DMSO / TFA) δ [ppm] 8.032 (m, 2H), 7.846 (d, 1H), 7.526 (m, 1H), 7.436 (m, 2H), 7.380 (m, 1H ), 7,329 (m, 1H), 7,274 (m, 2H), 7,196 (m, 1H), 1 4,980 (s, 2H), 4,816 (s, 2H), 3,939 (m, 2H).
Beispiel 13Example 13
Durch Umsetzung von "A130" mit den entsprechenden Aminen oder Alkoholen erhält man nach Bestrahlung in der Mikrowelle in Wasser und T/EP2008/004846By reaction of "A130" with the corresponding amines or alcohols is obtained after irradiation in the microwave in water and T / EP2008 / 004846
- 159 -- 159 -
anschließender Reinigung mittels HPLC die nachstehendensubsequent purification by HPLC the following
Verbindungen.Links.
Bei Umsetzung von "A130" mit den Aminen wird während der Reaktion vorzugsweise Kupfer(ll)-oxid, Oxalsäure-bis(Cyclohexylidenhydrazid),When reacting "A130" with the amines, preference is given to copper (II) oxide, oxalic acid bis (cyclohexylidene hydrazide) during the reaction,
Kalilauge und Tetra-n-butylammoniumbromid zugesetzt.Potassium hydroxide and tetra-n-butylammonium bromide added.
Bei Umsetzung von "A130" mit den Alkoholen wird während der Reaktion vorzugsweise Kupfer(l)iodid, Dimethylaminoessigsäure undWhen "A130" is reacted with the alcohols, copper (I) iodide, dimethylaminoacetic acid and
Cäsiumcarbonat zugesetzt, wobei die Reaktion vorzugsweise in dioxan durchgeführt wird.Cesium carbonate added, wherein the reaction is preferably carried out in dioxane.
Beispiel 14Example 14
Analog Beispiel 4.3 erhält man die Verbindung 2-Amino-7-chlor-4-(1 ,3- dihydro-isoindol-2-yl-carbonyl)-chinazolin ("A952") The compound 2-amino-7-chloro-4- (1,3-dihydro-isoindol-2-yl-carbonyl) quinazoline ("A952") is obtained analogously to Example 4.3.
Retentionszeit LC-MS: 1 ,909 min (Methode „Gradient polar"); Ausbeute: 140 mg (40%).Retention time LC-MS: 1.909 min ("gradient polar" method); yield: 140 mg (40%).
Analog werden die nachstehenden Verbindungen erhaltenAnalogously, the following compounds are obtained
P2008/004846 P2008 / 004846
-165- -165-
Beispiel 15Example 15
Herstellung von 2-Amino-6-(3-hydroxy-prop-1-inyl)-4-(1 ,3-dihydro-isoindol- 2-yl-carbonyl)-chinazolin ("A964")Preparation of 2-amino-6- (3-hydroxyprop-1-ynyl) -4- (1,3-dihydroisoindol-2-ylcarbonyl) quinazoline ("A964")
"A964""A964"
Zu einer Lösung von 2 g 2-Amino-6-iod-4-(1 ,3-dihydro-isoindol-2-yl- carbonyl)-chinazolin in 3 ml DMF unter Argon werden 3 ml Triethylamin, 368,7 μl 2-Propin-1-ol, 36,6 mg Kupfer(l)iodid und 67,5 mg Bis(triphenyl- phosphin)-palladium(ll)-chlorid (15,2% Palladium) gegeben. Es wird 48 h bei Raumtemperatur gerührt, mit 100 ml DCM versetzt und mehrmals wässrig extrahiert. Die organische Phase wurde getrocknet und unter vermindertem Druck am Rotationsverdampfer bis zur Trockene eingedampft. Der erhaltene Rückstand wird mit wenig ACN versetzt, wobei ein gelber Feststoff ausfällt. Filtrieren und Trocknen (Trockenschrank bei 400C) liefert 1.3 g "A964"; Retentionszeit LC-MS: 1 ,502 min (Methode „Gradient polar"); 1H NMR (500 MHz, DMSO/TFA): δ [ppm] 8.172 (d, 1H), 8.032 (dd, 1H), 7.764 (d, 1H), 7.466 (d, 1H), 7.362 (t, 1H), 7.318 (t, 1H), 7.256 (d, 1H), 5.070 (S12H), 4.859 (s, 2H), 4.342 (s, 2H).To a solution of 2 g of 2-amino-6-iodo-4- (1,3-dihydro-isoindol-2-yl-carbonyl) quinazoline in 3 ml of DMF under argon is added 3 ml of triethylamine, 368.7 μl of 2- Propyn-1-ol, 36.6 mg copper (I) iodide and 67.5 mg bis (triphenylphosphine) palladium (II) chloride (15.2% palladium). It is stirred for 48 h at room temperature, treated with 100 ml of DCM and extracted several times with aqueous. The organic phase was dried and evaporated to dryness under reduced pressure on a rotary evaporator. The resulting residue is treated with a little ACN, whereby a yellow solid precipitates. Filter and dry (oven at 40 0 C) provides 1.3 g of "A964"; Retention time LC-MS: 1.502 min ("gradient polar"method); 1 H NMR (500 MHz, DMSO / TFA): δ [ppm] 8,172 (d, 1H), 8,032 (dd, 1H), 7,764 (d, 1H), 7,466 (d, 1H), 7,362 (t, 1H) , 7.318 (t, 1H), 7.256 (d, 1H), 5.070 (S 1 2H), 4.859 (s, 2H), 4.342 (s, 2H).
Analog werden die nachstehenden Verbindungen erhaltenAnalogously, the following compounds are obtained
Beispiel 16Example 16
Herstellung von [2-Amino-4-(1 ,3-dihydro-isoindol-2-carbonyl)-chinazolin-6- yl]-propinal ("A965")Preparation of [2-amino-4- (1,3-dihydroisoindole-2-carbonyl) -quinazolin-6-yl] -propanal ("A965")
860 mg 2-Amino-6-(3-hydroxy-prop-1-inyl)-4-(1 ,3-dihydro-isoindol-2-yl- carbonyl)-chinazolin werden in 2 ml Tetra hydrofu ran gelöst und nach Zusatz von 1.736 g Mangan(IV)-oxid bei Raumtemperatur 16 h gerührt. Nach Zugabe von weiteren 434 mg Mangan(IV)-oxid wird weitere 12 h gerührt, über Kieselgur filtriert und das Filtrat zur Trockne eingeengt. Trocknen im Vakuum liefert 402 mg "A965". Beispiel 17860 mg of 2-amino-6- (3-hydroxy-prop-1-ynyl) -4- (1, 3-dihydro-isoindol-2-yl-carbonyl) quinazoline are dissolved in 2 ml of tetrahydrofuran and after addition of 1736 g of manganese (IV) oxide stirred at room temperature for 16 h. After addition of a further 434 mg of manganese (IV) oxide, the mixture is stirred for a further 12 h, filtered through kieselguhr and the filtrate is concentrated to dryness. Drying in vacuo gives 402 mg "A965". Example 17
Herstellung von 5-[2-Amino-4-(1 ,3-dihydro-isoindol-2-carbonyl)-chinazolin- 6-yl]-3H-[1 ,2,3]triazol-4-carbaldehyd ("A966")Preparation of 5- [2-amino-4- (1,3-dihydro-isoindole-2-carbonyl) quinazolin-6-yl] -3H- [1,2,3] triazole-4-carbaldehyde ("A966" )
402 mg "A965" werden in 0,5 ml DMSO gelöst. Zu dieser Lösung wird eine Lösung von 84 mg Natrumazid in 0,5 ml DMSO dazugegeben und 30 min bei Raumtemperatur gerührt. Die Lösung wird dann auf eine 15%ige KH2PO4-Lösung (5 ml) gegossen und mit Methyl-tert.-butylether extrahiert. Die organische Phase wird eingeengt. Ausbeute: 150 mg "A966".402 mg "A965" are dissolved in 0.5 ml DMSO. To this solution is added a solution of 84 mg of sodium azide in 0.5 ml of DMSO and stirred for 30 minutes at room temperature. The solution is then poured onto a 15% KH 2 PO 4 solution (5 ml) and extracted with methyl tert-butyl ether. The organic phase is concentrated. Yield: 150 mg "A966".
Beispiel 18Example 18
Herstellung von [2-Amino-6-(5-methylaminomethyl-1 H-[1 ,2,3]triazol-4-yl)- chinazolin-4-yl]-(1 ,3-dihydro-isoindol-2-yl)-methanon ("A967")Preparation of [2-Amino-6- (5-methylaminomethyl-1 H - [1, 2,3] triazol-4-yl) quinazolin-4-yl] - (1, 3-dihydro-isoindol-2-yl ) -methanone ("A967")
60 mg "A966" werden in 0,5 ml 1 ,2-Dichlorethan und 0,5 ml THF gelöst. Zu dieser Lösung gibt man 0.156 ml Methylamin (2 M in THF), 8.9 μl Eisessig und rührt 6 h bei 5O0C. Nach Abkühlen auf Raumtemperatur werden 43 mg Natriumtriacetoxyborhydrid dazu gegeben und 16 h bei RT gerührt. Anschließend wird das Reaktionsgemisch auf Wasser gegossen und mit Dichlormethan extrahiert, die vereinigten organischen Phasen getrocknet, filtriert und zur Trockne eingedampft. Chromatographie an Kieselgel liefert "A967"; Ausbeute: 10 mg; Retentionszeit LC-MS: 1 ,182 min (Methode „Gradient polar"); 1H NMR (500 MHz, DMSO/TFA): δ [ppm] 8.344 (dd, 1H), 8.287 (d, 1H), 7.896 (d, 1H), 7.475 (d, 1H), 7.363 (t, 1H), 7.318 (t, 1H), 7.266 (d, 1H), 5.074 (s, 2H), 4.885 (s, 2H), 4.444 (d, 2H), 2.669 (t, 3H).60 mg of "A966" are dissolved in 0.5 ml of 1,2-dichloroethane and 0.5 ml of THF. 0.156 ml of methylamine (2 M in THF), 8.9 μl, are added to this solution Glacial acetic acid and stirred for 6 h at 5O 0 C. After cooling to room temperature, 43 mg of sodium triacetoxyborohydride are added and stirred for 16 h at RT. The reaction mixture is then poured into water and extracted with dichloromethane, the combined organic phases dried, filtered and evaporated to dryness. Chromatography on silica gel provides "A967"; Yield: 10 mg; Retention time LC-MS: 1.182 min ("gradient polar"method); 1H NMR (500 MHz, DMSO / TFA): δ [ppm] 8.344 (dd, 1H), 8.287 (d, 1H), 7.896 (d, 1H), 7.475 (d, 1H), 7.363 (t, 1H), 7.318 (t, 1H), 7.266 (d, 1H), 5.074 (s, 2H), 4.885 (s, 2H), 4.444 (d, 2H ), 2.669 (t, 3H).
Beispiel 19Example 19
Herstellung von [2-Amino-6-(5-hydroxymethyl-1H-[1 ,2,3]triazol-4-yl)- chinazolin-4-yl]-(1 ,3-dihydro-isoindol-2-yl)-methanon ("A968")Preparation of [2-amino-6- (5-hydroxymethyl-1H- [1,2,3] triazol-4-yl) -quinazolin-4-yl] - (1,3-dihydro-isoindol-2-yl) -methanone ("A968")
60 mg "A966" werden in 1 ml Tetrahydrofuran gelöst. Zu dieser Lösung gibt man 43 mg Natriumtriacetoxyborhydrid und rührt 16 h bei RT. Anschließend wird das Reaktionsgemisch auf Wasser gegossen und mit Dichlormethan extrahiert, die vereinigten organischen Phasen getrocknet, filtriert und zur Trockne eingedampft. Chromatographie an Kieselgel liefert "A968"; Ausbeute: 2,1 mg; Retentionszeit LC-MS: 1 ,320 min (Methode „Gradient polar"). Beispiel 2060 mg "A966" are dissolved in 1 ml of tetrahydrofuran. 43 mg of sodium triacetoxyborohydride are added to this solution and the mixture is stirred at RT for 16 h. The reaction mixture is then poured into water and extracted with dichloromethane, the combined organic phases dried, filtered and evaporated to dryness. Chromatography on silica gel yields "A968"; Yield: 2.1 mg; Retention time LC-MS: 1, 320 min ("Gradient polar" method). Example 20
Herstellung von 2-[2-Amino-4-(1 ,3-dihydro-isoindol-2-carbonyl)-chinazolin- 6-yl]-benzaldehyd ("A969")Preparation of 2- [2-amino-4- (1,3-dihydro-isoindole-2-carbonyl) quinazolin-6-yl] -benzaldehyde ("A969")
1 g "A130" werden in 10 ml Ethanol gelöst. Man gibt 468,3 mg 2-Formyl- phenylboronsäure, 664 mg Kaliumcarbonat, 58,9 mg [1 ,1'-Bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll) und 3 ml Wasser zu dieser Lösung und erhitzt unter Argon für 30 min auf 1300C. Hierbei bildet sich ein Niederschlag, der filtriert und im Trockenschrank bei 500C für 12 h getrocknet wird. Das entstandene Produkt wird ohne weitere Reinigung weiter umgesetzt. Ausbeute 910 mg 2-[2-Amino-4-(1 ,3-dihydro-isoindol-2- carbonyl)-chinazolin-6-yl]-benzaldehyd ("A969"); Retentionszeit LC-MS: 1 ,863 min (Methode „Gradient polar").1 g of "A130" are dissolved in 10 ml of ethanol. 468.3 mg of 2-formylphenylboronic acid, 664 mg of potassium carbonate, 58.9 mg of [1,1'-bis (diphenylphosphino) ferrocenes] dichloropalladium (II) and 3 ml of water are added to this solution and heated under argon 30 min at 130 0 C. This forms a precipitate, which is filtered and dried in a drying oven at 50 0 C for 12 h. The resulting product is further reacted without further purification. Yield 910 mg of 2- [2-amino-4- (1,3-dihydroisoindole-2-carbonyl) quinazolin-6-yl] benzaldehyde ("A969"); Retention time LC-MS: 1.863 min ("gradient polar" method).
Beispiel 21Example 21
Herstellung von {2-Amino-6-[2-(4-methyl-piperazin-1 -ylmethyl)-phenyl]- chinazolin-4-yl}-(1 ,3-dihydro-isoindol-2-yl)-methanon ("A970")Preparation of {2-Amino-6- [2- (4-methylpiperazin-1-ylmethyl) phenyl] -quinazolin-4-yl} - (1,3-dihydro-isoindol-2-yl) -methanone ( "A970")
"A970" 60 mg "A969" werden in 1 ml 1 ,2-Dichlorethan und 1 ml Tetrahydrofuran gelöst. Man gibt 18,6 μl 1-Methylpiperazin und 8,7 μl Eisessig dazu und rührt 30 min bei 25°C. Nun werden 42 mg Nathumtriacetoxyborhydrid zugegeben und weitere 3 h bei 25°C gerührt. Man gießt auf Wasser, extrahiert dreimal mit Dichlormethan und trocknet die vereinigten organischen Phasen über Natriumsulfat. Nach Filtration wird das Filtrat zur"A970" 60 mg of "A969" are dissolved in 1 ml of 1,2-dichloroethane and 1 ml of tetrahydrofuran. 18.6 μl of 1-methylpiperazine and 8.7 μl of glacial acetic acid are added and the mixture is stirred at 25.degree. C. for 30 minutes. Now 42 mg Nathumtriacetoxyborhydrid are added and stirred at 25 ° C for a further 3 h. It is poured into water, extracted three times with dichloromethane and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate becomes
Trockne eingeengt und chromatographisch (reversed phase HPLC) gereinigt.Dry concentrated and purified by chromatography (reversed phase HPLC).
Ausbeute: 27 mg (37%) "A970";Yield: 27 mg (37%) "A970";
Retentionszeit LC-MS: 1,478 min (Methode „Gradient polar");Retention time LC-MS: 1.478 min ("gradient polar" method);
1H NMR (500 MHz, DMSO/TFA) δ [ppm] 8.090 (d, 1H), 8.028 (dd, 1H), 1 H NMR (500 MHz, DMSO / TFA) δ [ppm] 8,090 (d, 1H), 8,028 (dd, 1H),
7.840 (d, 1 H), 7.709-7.691 (m, 1 H), 7.550-7.532 (m, 2H), 7.415-7.385 (m,7,840 (d, 1H), 7,709-7,691 (m, 1H), 7,550-7,532 (m, 2H), 7,415-7,385 (m,
2H), 7.331-7.270 (m, 2H), 7.219 (d, 1 H), 4.997 (s, 2H), 4.801 (s, 2H),2H), 7,331-7,270 (m, 2H), 7,219 (d, 1H), 4,997 (s, 2H), 4,801 (s, 2H),
4.197 (s, 2H), 3.607-2.966 (m, 8H), 2.795 (s, 3H).4,197 (s, 2H), 3,607-2,966 (m, 8H), 2,795 (s, 3H).
Analog werden die nachstehenden Verbindungen erhaltenAnalogously, the following compounds are obtained
Beispiel 22 Example 22
Herstellung von {2-Amino-6-[2-(4-methyl-piperazin-1-sulfonyl)-phenyl]- chinazolin-4-yl}-(1 ,3-dihydro-isoindol-2-yl)-methanon ("A980")Preparation of {2-Amino-6- [2- (4-methyl-piperazine-1-sulfonyl) -phenyl] -quinazolin-4-yl} - (1,3-dihydro-isoindol-2-yl) -methanone ( "A980")
22.1 Herstellung der Vorstufe22.1 Preparation of the precursor
[2-Amino-6-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-chinazolin-4-yl]- (1 ,3-dihydro-isoindol-2-yl)-methanon[2-Amino-6- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) quinazolin-4-yl] - (1,3-dihydroisoindole-2-yl) yl) -methanone
8 g "A130" werden unter Argonatmosphäre in 100 ml Dimethylsulfoxid gelöst. Man gibt 5,37 g Bis(pinacolato)diboron, 6,414 g Kaliumacetat und 785 mg [1 ,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) zu dieser Lösung und erhitzt für 60 min auf 800C. Nach Abkühlen wird das Gemisch mit 250 ml Diethylether versetzt und viermal gegen je 100 ml Wasser extrahiert. Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet, filtriert und das Filtrat eingeengt, bis ein rotes Öl vorliegt. Dieses Öl wird mit Acetonitril verrieben, wobei hell-beige Kristalle entstehen. Filtrieren über eine Saugnutsche und Trocknen bei 400C im Vakuum liefert das Produkt.8 g of "A130" are dissolved under argon atmosphere in 100 ml of dimethyl sulfoxide. 5.37 g of bis (pinacolato) diboron, 6.414 g of potassium acetate and 785 mg of [1,1'-bis (diphenylphosphino) ferrocenes] dichloropalladium (II) are added to this solution and heated to 80 ° C. for 60 min The mixture is mixed with 250 ml of diethyl ether and extracted four times against 100 ml of water. The combined organic phases are dried over sodium sulfate, filtered and the filtrate is concentrated until a red oil is present. This oil is triturated with acetonitrile to give light beige crystals. Filtration through a suction filter and drying at 40 0 C in vacuo provides the product.
Hierbei bildet sich ein Niederschlag, der filtriert und im Trockenschrank bei 500C für 12 h getrocknet wird. Das entstandene Produkt wird ohne weitere Reinigung weiter umgesetzt.This forms a precipitate, which is filtered and dried in a drying oven at 50 0 C for 12 h. The resulting product is further reacted without further purification.
Ausbeute: 3,4 g [2-Amino-6-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- chinazolin-4-yl]-(1,3-dihydro-isoindol-2-yl)-methanon; Retentionszeit LC-MS: 2,077 min (Methode „Gradient polar"). 22.2Yield: 3.4 g of [2-amino-6- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) quinazolin-4-yl] - (1,3- dihydro-isoindol-2-yl) -methanone; Retention time LC-MS: 2.077 min ("gradient polar" method). 22.2
150 mg [2-Amino-6-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- chinazolin-4-yl]-(1 ,3-dihydro-isoindol-2-yl)-methanon werden unter Argonatmosphäre in 3 ml Ethanol gelöst. Man gibt 115 mg 1-(2-Brom- benzenesulfonyl)-4-methyl-piperazin, 0,1 g Kaliumcarbonat, 1 ml Wasser und 14,7 mg [1 ,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) zu dieser Lösung und erhitzt für 30 min auf 8O0C. Es wird heiß über Kieselgur abgesaugt und das Filtrat eingeengt. Der erhaltene Rückstand wird in 3,8 ml ACN gelöst und chromatographisch an einer reversed-phase Säule getrennt.150 mg of [2-amino-6- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) quinazolin-4-yl] (1,3-dihydroisoindole) 2-yl) -methanone are dissolved under argon atmosphere in 3 ml of ethanol. 115 mg of 1- (2-bromobenzenesulfonyl) -4-methylpiperazine, 0.1 g of potassium carbonate, 1 ml of water and 14.7 mg of [1,1'-bis (diphenylphosphino) ferrocenes] dichloropalladium (II) are to this solution and heated for 30 min to 8O 0 C. It is filtered off with suction through kieselguhr hot and the filtrate was concentrated. The residue obtained is dissolved in 3.8 ml of ACN and separated by chromatography on a reversed-phase column.
Ausbeute: 62 mg {2-Amino-6-[2-(4-methyl-piperazine-1-sulfonyl)-phenyl]- chinazolin-4-yl}-(1,3-dihydro-isoindol-2-yl)-methanon ("A980"); Retentionszeit LC-MS: 1 ,574 min (Methode „Gradient polar"); 1H NMR (500 MHz, DMSO/TFA): δ [ppm] 8.033 (dd, 1 H), 8.006-7.987 (m, 2H), 7.787-7.757 (m, 2H), 7.695 (t, 1H), 7.444-7.403 (m, 2H), 7.341-7.282 (m, 2H), 7.244 (d, 1H), 4.995 (s, 2H), 4.825 (s, 2H), 3.341 (m, 4H), 2.939 (m, 4H), 2.805 (s, 3H).Yield: 62 mg of {2-amino-6- [2- (4-methyl-piperazine-1-sulfonyl) -phenyl] -quinazolin-4-yl} - (1,3-dihydro-isoindol-2-yl) - methanone ("A980"); Retention time LC-MS: 1. 574 min ("gradient polar" method); 1 H NMR (500 MHz, DMSO / TFA): δ [ppm] 8.033 (dd, 1H), 8.006-7.987 (m, 2H), 7.787 -7.757 (m, 2H), 7.695 (t, 1H), 7.444-7.403 (m, 2H), 7.341-7.282 (m, 2H), 7.244 (d, 1H), 4.995 (s, 2H), 4.825 (s , 2H), 3,341 (m, 4H), 2,939 (m, 4H), 2,805 (s, 3H).
Analog werden die nachstehenden Verbindungen erhaltenAnalogously, the following compounds are obtained
Beispiel 23 Example 23
Herstellung von {2-Amino-6-[2-(4-methyl-piperazin-1-carbonyl)-phenyl]- chinazolin-4-yl}-(1 ,3-dihydro-isoindol-2-yl)-methanon ("A983")Preparation of {2-Amino-6- [2- (4-methyl-piperazine-1-carbonyl) -phenyl] -quinazolin-4-yl} - (1,3-dihydro-isoindol-2-yl) -methanone ( "A983")
23.1 Herstellung der Vorstufe23.1 Preparation of the precursor
2-[2-Amino-4-(1 ,3-dihydro-isoindol-2-carbonyl)-chinazolin-6-yl]- benzoesäure ("A304")2- [2-Amino-4- (1,3-dihydroisoindole-2-carbonyl) quinazolin-6-yl] benzoic acid ("A304")
Zu einer Lösung von 300 mg 2-Amino-6-iod-4-(1 ,3-dihydro-isoindol-2-yl- carbonyl)-chinazolin ("A130") in 10 ml Ethanol unter Argon werden 266 mg 2-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzoesäure-ethylester, 399 mg Kaliumcarbonat, 3 ml Wasser und 17,7 mg [1 ,1 '-Bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll) gegeben. Es wird für 30 min auf 1200C erhitzt, wobei eine klare Lösung entsteht. Es wird heiß über Kieselgur filtriert. Beim Abkühlen kristallisiert 2-[2-Amino-4-(1 ,3-dihydro- isoindol-2-carbonyl)-chinazolin-6-yl]-benzoesäure-ethylester aus (Retentionszeit LC-MS: 2,056 min; Methode „ Gradient polar"). Man nimmt in 10 ml Natronlauge (2 N) auf und rührt 12 h bei 250C. Es wird dreimal mit je 10 ml Diethylether extrahiert, die wässrige Phase auf pH7 gestellt und wieder mit je 10 ml Diethylether extrahiert. Die organische Phase wird über Natriumsulfat getrocknet und filtriert, das Filtrat im Vakuum zur Trockne eingeengt.To a solution of 300 mg of 2-amino-6-iodo-4- (1,3-dihydro-isoindol-2-yl-carbonyl) -quinazoline ("A130") in 10 ml of ethanol under argon, 266 mg of 2- ( Ethyl 4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) benzoate, 399 mg potassium carbonate, 3 ml water and 17.7 mg [1, 1 'bis (diphenyl) phosphino) ferrocenes] dichloropalladium (II). It is heated for 30 min at 120 0 C, whereby a clear solution is formed. It is filtered hot on diatomaceous earth. On cooling, 2- [2-amino-4- (1,3-dihydro-isoindole-2-carbonyl) quinazolin-6-yl] -benzoic acid ethyl ester crystallizes out (retention time LC-MS: 2.056 min, method "gradient polar It is taken up in 10 ml of sodium hydroxide solution (2 N) and stirred for 12 h at 25 0 C. It is extracted three times with 10 ml of diethyl ether, the aqueous phase is adjusted to pH 7 and extracted again with 10 ml of diethyl ether Phase is dried over sodium sulfate and filtered, the filtrate concentrated in vacuo to dryness.
Ausbeute: 180 mg "A304"; Retentionszeit LC-MS: 1 ,707 min (Methode „Gradient polar"); 1H NMR (500 MHz1 DMSO/TFA): δ [ppm] 8.005-7.985 (m, 2H), 7.891 (d, 1 H), 7.748 (d, 1 H), 7.598 (t, 1 H), 7.499 (t, 1 H), 7.415-7.389 (m, 2H), 7.327- 7.254 (m, 2H), 7.233 (d, 1 H), 4.993 (s, 2H), 4.837 (s, 2H).Yield: 180 mg "A304"; Retention time LC-MS: 1, 707 min ("gradient polar"method); 1 H NMR (500 MHz 1 DMSO / TFA): δ [ppm] 8,005-7,985 (m, 2H), 7,891 (d, 1H), 7,748 (d, 1H), 7,598 (t, 1H), 7,499 (t, 1H), 7,415-7,389 (m, 2H), 7,327-2,254 (m, 2H), 7,233 (d, 1H), 4,993 (s, 2H), 4,837 (s, 2H).
23.223.2
Zu einer Lösung von 90 mg 2-[2-Amino-4-(1 ,3-dihydro-isoindol-2- carbonyl)-chinazolin-6-yl]-benzoesäure in 1 ml Dimethylformamid werden 98,6 mg O^BenzotriazoM-yO-N.N.N'.N'-tetramethyluronium tetrafluoroborate (TBTU), 82,9 μl 1-Methylpiperazin und 140,7 μl 4- Methylmorpholin gegeben. Anschließend wird für 12 h bei 250C gerührt. Es wird im Vakuum zur Trockne eingeengt, in 1 ml Dimethylsulfoxid aufgenommen und chromatographisch (reversed phase HPLC) gereinigt. Ausbeute: 48 mg {2-Amino-6-[2-(4-methyl-piperazin-1-carbonyl)-phenyl]- chinazolin-4-yl}-(1 ,3-dihydro-isoindol-2-yl)-methanon ("A983"); Retentionszeit LC-MS: 1 ,432 min (Methode „Gradient polar"); 1H NMR (500 MHz, DMSO/TFA: δ [ppm] 8.076 (dd, 1 H), 7.992 (d, 1H), 7.835 (d, 1H), 7.586-7.475 (m, 4H), 7.427 (d, 1 H), 7.350-7.275 (m, 2H), 7.225 (d, 1 H), 5.012 (s, 2H), 4.781 (s, 2H), 3.708-2.974 (m, 11 H).To a solution of 90 mg of 2- [2-amino-4- (1,3-dihydro-isoindole-2-carbonyl) -quinazolin-6-yl] -benzoic acid in 1 ml of dimethylformamide is added 98.6 mg of O ^ -benzotriazomethane. yO-NNN'.N'-tetramethyluronium tetrafluoroborate (TBTU), 82.9 μl of 1-methylpiperazine and 140.7 μl of 4-methylmorpholine. The mixture is then stirred at 25 0 C for 12 h. It is concentrated to dryness in vacuo, taken up in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC). Yield: 48 mg {2-amino-6- [2- (4-methyl-piperazine-1-carbonyl) -phenyl] -quinazolin-4-yl} - (1,3-dihydro-isoindol-2-yl) - methanone ("A983"); Retention time LC-MS: 1.432 min ("gradient polar"method); 1 H NMR (500 MHz, DMSO / TFA: δ [ppm] 8.076 (dd, 1 H), 7.992 (d, 1H), 7.835 (d, 1H), 7,586-7,475 (m, 4H), 7,427 (d, 1H), 7,350-7,275 (m, 2H), 7,225 (d, 1H), 5,012 (s, 2H), 4,781 (s, 2H) , 3,708-2,974 (m, 11H).
Analog werden die nachstehenden Verbindungen erhaltenAnalogously, the following compounds are obtained
P2008/004846 P2008 / 004846
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Beispiel 24Example 24
Herstellung von {2-Amino-6-[2-(2-dimethylamino-ethoxy)-phenyl]- chinazolin-4-yl}-(1 ,3-dihydro-isoindol-2-yl)-methanon ("A986")Preparation of {2-Amino-6- [2- (2-dimethylamino-ethoxy) -phenyl] -quinazolin-4-yl} - (1,3-dihydro-isoindol-2-yl) -methanone ("A986")
24.1 Herstellung der Vorstufe [2-Amino-6-(2-hydroxy-phenyl)-chinazolin- 4-yl]-(1 ,3-dihydro-isoindol-2-yl)-methanon ("A335")24.1 Preparation of Precursor [2-Amino-6- (2-hydroxyphenyl) -quinazolin-4-yl] - (1,3-dihydro-isoindol-2-yl) -methanone ("A335")
Zu einer Lösung von 100 mg 2-Amino-6-iod-4-(1 ,3-dihydro-isoindol-2-yl- carbonyl)-chinazolin in 3 ml Ethanol unter Argon werden 39,8 mg 2-To a solution of 100 mg of 2-amino-6-iodo-4- (1,3-dihydro-isoindol-2-yl-carbonyl) quinazoline in 3 ml of ethanol under argon is added 39.8 mg of 2-
Hydroxybenzolboronsäure, 100 mg Kaliumcarbonat, 4,2 μl Wasser undHydroxybenzeneboronic acid, 100 mg of potassium carbonate, 4.2 ul of water and
9,8 mg [1 ,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) gegeben. Es wird für 12 h auf 800C erhitzt. Es wird im Vakuum zurAdded 9.8 mg of [1,1'-bis (diphenylphosphino) ferrocenes] dichloropalladium (II). It is heated to 80 ° C. for 12 h. It is used in a vacuum
Trockne eingeengt, in 1 ml Dimethylsulfoxid aufgenommen und chromatographisch (reversed phase HPLC) gereinigt.Dry concentrated, taken up in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Ausbeute: 20 mg [2-Amino-6-(2-hydroxy-phenyl)-chinazolin-4-yl]-(1 ,3- dihydro-isoindol-2-yl)-methanon ("A335");Yield: 20 mg of [2-amino-6- (2-hydroxy-phenyl) -quinazolin-4-yl] - (1,3-dihydro-isoindol-2-yl) -methanone ("A335");
Retentionszeit LC-MS: 1 ,817 min (Methode „Gradient polar");Retention time LC-MS: 1.817 min ("gradient polar" method);
1H NMR (500 MHz, DMSO/TFA): d [ppm] 8.273 (dd, 1H), 8.169 (d, 1H), 1 H NMR (500 MHz, DMSO / TFA): d [ppm] 8.273 (dd, 1H), 8.169 (d, 1H),
7.788 (d, 1H), 7.430 (d, 1 H), 7.340-7.185 (m, 5H), 6.964 (d, 1 H), 6.897 (t,7,788 (d, 1H), 7,430 (d, 1H), 7,340-7,185 (m, 5H), 6,964 (d, 1H), 6,897 (t,
1H), 5.015 (s, 2H), 4.828 (s, 2H).1H), 5.015 (s, 2H), 4.828 (s, 2H).
24.2 24.2
Zu einer Lösung von 100 mg [2-Amino-6-(2-hydroxy-phenyl)-chinazolin-4- yl]-(1 ,3-dihydro-isoindol-2-yl)-methanon in 5 ml Acetonitril werden 41 ,4 mg (2-Chloro-ethyl)-dimethyl-amin (hydrochlorid) und 170,4 mg Cäsiumcarbonat gegeben. Es wird für 1 h auf 800C erhitzt, vom Niederschlag filtriert und anschließend das Filtrat im Vakuum zur Trockne eingeengt, in 1 ml Dimethylsulfoxid aufgenommen und chromatographisch (reversed phase HPLC) gereinigt.To a solution of 100 mg of [2-amino-6- (2-hydroxy-phenyl) -quinazolin-4-yl] - (1,3-dihydro-isoindol-2-yl) -methanone in 5 ml of acetonitrile are added 4 mg of (2-chloro-ethyl) -dimethyl-amine (hydrochloride) and 170.4 mg of cesium carbonate. It is heated for 1 h at 80 0 C, filtered from the precipitate and then the filtrate concentrated in vacuo to dryness, taken up in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Ausbeute: 68 mg {2-Amino-6-[2-(2-dimethylamino-ethoxy)-phenyl]- chinazolin-4-yl}-(1 ,3-dihydro-isoindol-2-yl)-methanon ("A986"); Retentionszeit LC-MS: 1 ,567 min (Methode „Gradient polar"); 1H NMR (500 MHz, DMS(VTFA): d [ppm] 8.230 (dd, 1 H), 8.115 (s, 1 H), 7.866 (d, 1H), 7.485-7.413 (m, 3H), 7.372-7.292 (m, 2H), 7.249 (t, 1H), 7.149 (t, 1 H), 5.096 (s, 2H), 4.892 (s, 2H), 4.431 (t, 2H), 3.629 (t, 2H), 2.854 (s, 6H).Yield: 68 mg of {2-amino-6- [2- (2-dimethylamino-ethoxy) -phenyl] -quinazolin-4-yl} - (1,3-dihydro-isoindol-2-yl) -methanone ("A986 "); Retention time LC-MS: 1. 567 min ("gradient polar" method); 1H NMR (500 MHz, DMS (VTFA): d [ppm] 8.230 (dd, 1H), 8.115 (s, 1H), 7.866 ( d, 1H), 7,485-7,413 (m, 3H), 7,372-7,292 (m, 2H), 7,249 (t, 1H), 7,149 (t, 1H), 5,096 (s, 2H), 4,892 (s, 2H ), 4,431 (t, 2H), 3,629 (t, 2H), 2,854 (s, 6H).
Analog erhält manAnalog obtained
Beispiel 25Example 25
Durch Umsetzung von 2-Amino-6-(2-carboxy-ethyl)-4-(1 ,3-dihydro-isoindol- 2-yl-carbonyl)-chinazolin ("A143a") mit den entsprechenden Aminen erhält man nachstehende VerbindungenBy reacting 2-amino-6- (2-carboxy-ethyl) -4- (1, 3-dihydro-isoindol-2-yl-carbonyl) -quinazoline ("A143a") with the corresponding amines, the following compounds are obtained
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines erfindungsgemäßen Wirkstoffes und 5 g Dinatriumhydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abge- füllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.A solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 2 l of twice-distilled water with 2N hydrochloric acid, filtered sterile, filled into injection vials, lyophilized under sterile conditions and closed under sterile conditions. Each injection jar contains 5 mg of active ingredient.
Beispiel B: Suppositorien Man schmilzt ein Gemisch von 20 g eines erfindungsgemäßen Wirkstoffes mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.Example B: Suppositories A mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
Beispiel C: LösungExample C: Solution
Man bereitet eine Lösung aus 1 g eines erfindungsgemäßen Wirkstoffes,A solution of 1 g of an active ingredient according to the invention is prepared,
9,38 g NaH2PO4 • 2 H2O, 28,48 g Na2HPO4 • 12 H2O und 0,1 g Benzalkoniumchlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.9.38 g of NaH 2 PO 4 • 2H 2 O, 28.48 g of Na 2 HPO 4 • 12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.
Beispiel D: SalbeExample D: Ointment
Man mischt 500 mg eines erfmdungsgemäßen Wirkstoffes mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient according to the invention are mixed with 99.5 g of Vaseline under aseptic conditions.
Beispiel E: TablettenExample E: Tablets
Ein Gemisch von 1 kg Wirkstoff, 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält. Beispiel F: DrageesA mixture of 1 kg of active ingredient, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way into tablets, such that each tablet contains 10 mg of active ingredient. Example F: dragees
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicherAs in Example E tablets are pressed, which are then in the usual
Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Be coated with a coating of sucrose, potato starch, talc, tragacanth and dye.
Beispiel G: KapselnExample G: Capsules
2 kg Wirkstoff werden in üblicher weise in Hartgelatine kapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient are capsules usually filled in hard gelatin, so that each capsule contains 20 mg of the active ingredient.
Beispiel H: AmpullenExample H: Ampoules
Eine Lösung von 1 kg eines erfindungsgemäßen Wirkstoffes in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. A solution of 1 kg of an active ingredient according to the invention in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

Claims

Patentansprücheclaims
1. Verbindungen der Formel I1. Compounds of the formula I
worinwherein
R1 H1 A, (CH2)nCONH2, (CH2)nCONHA, (CHzJnCONAA1,R 1 H 1 A, (CH 2 ) nCONH 2 , (CH 2 ) n CONHA, (CHzJnCONAA 1 ,
HaI, (CH2)πNH2, (CH2)nNHA, (CH2)nNAA\ CN, NO2, (CH2)nAr, OAr, (CH2)nCOOH, (CH2)nCOOA, (CH2)nOH, (CH2)nOA, (CH2)nHet, COHet, C=C-CH2SiA2A1, C≡CH, C≡C-A, CH=CH-Ar1, CH=CH-COOA1 0 CH2CH(OH)CH2OH, O(CH2)nOH, NH(CH2)nOH,Hal, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA \ CN, NO 2 , (CH 2 ) n Ar, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA , (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het, COHet, C =C-CH 2 SiA 2 A 1 , C≡CH, C≡CA, CH = CH-Ar 1 , CH = CH-COOA 1 O CH 2 CH (OH) CH 2 OH, O (CH 2 ) n OH, NH (CH 2 ) n OH,
O(CH2)nOA, NH(CH2)nOA, O(CH2)nNHA, NH(CH2)nNHA, NR4R5, (CH2)nCOOA, (CH2)nCONH(CH2)2CN, NH(CH2)nAr oder CH=CH-COOH, 5 R2 H, A, (CH2)nAr, (CH2)nHet, (CH2)nOH, (CH2)nOA,O (CH 2 ) n OA, NH (CH 2 ) n OA, O (CH 2 ) n NHA, NH (CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH (CH 2 ) 2 CN, NH (CH 2 ) n Ar or CH = CH-COOH, 5 R 2 H, A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n OH, ( CH 2 ) n OA,
(CH2)nNHHet, (CH2)nSA oder (CH2)nCH(OH)Ar,(CH 2 ) n NHHet, (CH 2 ) n SA or (CH 2 ) n CH (OH) Ar,
R3 A, (CH2)nAr, (CH2)nHet, (CH2)nCN, (CH2)nNH2,R 3 A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n CN, (CH 2 ) n NH 2 ,
(CH2)nNHA, (CHz)nNAA1, (CH2)nOH, (CH2)nOA oder(CH 2 ) n NHA, (CHz) n NAA 1 , (CH 2 ) n OH, (CH 2 ) n OA or
(CH2)nNHHet, 0(CH 2 ) n NHHet, 0
R und R zusammen mit dem N-Atom an das sie gebunden sind, auch einen unsubstituierten oder ein-, zwei- oder dreifach durch HaI, A, (CH2)nOH, (CH2)nOA und/oder =O (Carbonylsauerstoff) substituierten gesättigten, $ ungesättigten oder aromatischen mono- oder bicyclischen Heterocyclus, der weitere 1 bis 3 N-, O- und/oder S-Atome enthalten kann, R4, R5 jeweils unabhängig voneinander (CH2)nOH, (CH2)nOA,R and R together with the N-atom to which they are attached are also unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and / or = O ( Carbonyl oxygen) substituted saturated, unsaturated or aromatic mono- or bicyclic heterocycle which may contain an additional 1 to 3 N, O and / or S atoms, R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
(CH2)nNH2, (CH2)nNHA oder (CH2JnNAA1 ,(CH 2 ) n NH 2 , (CH 2 ) n NHA or (CH 2 J n NAA 1 ,
Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI1 (CH2)nOA, (CH2)nOH, (CH2)nCN, SA1 SOA, SO2A1 NO2, C≡CH, (CH2)nCOOH, CHO, (CH2)nCOOA, CONH2, CONHA, CONAA1, NHCOA, CH(OH)A, (CH2JnNH2, (CH2)nNHA, (CH2)nNAA',Ar is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal 1 (CH 2 ) n OA, (CH 2 ) n OH, (CH 2 ) n CN, SA 1 SOA, SO 2 A 1 NO 2 , C≡CH, (CH 2 ) n COOH, CHO, (CH 2 ) n COOA, CONH 2 , CONHA, CONAA 1 , NHCOA, CH (OH) A, (CH 2 J n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA ',
(CH2)nNAAr1, O(CH2)nHet1, (CH2)nHet1, COO(CH2)nAr1, (CH2)nNHSO2A, (CH2)nOAr1, O(CH2)nAr1, SO2NH(CH2)nNH2, SO2NH2, SO2NHA, SO2NAA", CONHAr1, CONH(CH2)nCOOA, CONH(CH2)nCOOH,(CH 2 ) n NAAr 1 , O (CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO (CH 2 ) n Ar 1 , (CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 , O (CH 2 ) n Ar 1 , SO 2 NH (CH 2 ) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA ", CONHAr 1 , CONH (CH 2 ) n COOA, CONH (CH 2 ) n COOH,
NHCO(CH2)nCOOA, NHCO(CH2)nCOOH, CONH(CH2)nNH2l CONH(CH2)nNHA, CONH(CH2)nNAA\ CONH(CH2)nCN, NHCOHet, SO2Het, COHet und/oderNHCO (CH 2 ) n COOA, NHCO (CH 2 ) n COOH, CONH (CH 2 ) n NH 2l CONH (CH 2 ) n NHA, CONH (CH 2 ) n NAA \ CONH (CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and / or
(CH2)nCH(NH2)COOH substituiertes Phenyl, Naphthyl,(CH 2 ) n CH (NH 2 ) COOH substituted phenyl, naphthyl,
Tetrahydronaphthyl oder Biphenyl,Tetrahydronaphthyl or biphenyl,
Ar1 unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A1 HaI und/oder OA substituiertes Phenyl, Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch A, (CH2)nOA, (CH2)nOH, Ar1, SH, S(O)mA, HaI, NO2, CN, COA1 CHO1 COOA1 COOBenzyl,Ar 1 is unsubstituted or mono-, di-, tri-, tetra- or quintuply phenyl substituted by A 1 Hal and / or OA; Het is a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N-, O- and or S atoms which are unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S (O) m A, Hal, NO 2 , CN, COA 1 CHO 1 COOA 1 COOBenzyl,
CONH2, CONHA1 CONAA1, SO2NH2, (CH2)nNH2l (CH2)nNHA, (CH2)nNAA', NHSO2A und/oder =0 (Carbonylsauerstoff) substituiert sein kann,CONH 2 , CONHA 1 CONAA 1 , SO 2 NH 2 , (CH 2 ) n NH 2l (CH 2 ) n NHA, (CH 2 ) n NAA ', NHSO 2 A and / or = 0 (carbonyl oxygen) may be substituted,
Het1 einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der unsubstituiert oder ein- oder zweifach durch A, OA1 OH, HaI, CN und/oder =O (Carbonylsauerstoff) substituiert sein kann, A, A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-10 C-Atomen, worin 1-3 nicht- benachbarte CH2-Gruppen durch O, S, SO, SO2, NH,Het 1 is a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono- or binuclear may be substituted twice by A, OA 1 OH, Hal, CN and / or = O (carbonyl oxygen), A, A 'each independently of one another unbranched or branched alkyl having 1-10 C atoms, wherein 1-3 non-adjacent CH 2 groups by O, S, SO, SO 2 , NH,
NMe oder NEt und/oder auch 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können,NMe or NEt and / or also 1-5 H atoms can be replaced by F, OH and / or Cl,
Alk1, cyclisches Alkyl mit 3-8 C-Atomen oder0 Cycloalkylalkylen, worin 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können, Alk1 Alkenyl oder Alkinyl mit 2-6 C-Atomen, m 0, 1 oder 2, 5 n 0, 1 , 2, 3 oder 4, bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allenAlk 1 , cyclic alkyl having 3-8 C atoms or0 cycloalkylalkylene, in which 1-5 H atoms may be replaced by F, OH and / or Cl, Alk 1 alkenyl or alkynyl having 2-6 C atoms, m 0, 1 or 2, 5 n is 0, 1, 2, 3 or 4, as well as their pharmaceutically acceptable derivatives, salts, solvates and stereoisomers, including mixtures thereof in all
Verhältnissen. 0Conditions. 0
2. Verbindungen nach Anspruch 1 , worin2. Compounds according to claim 1, wherein
Het unsubstituiertes oder ein-, zwei- oder dreifach durch A,Het unsubstituted or one, two or three times by A,
(CH2)nOA, (CH2)nOH, Ar1, SH, S(O)mA, HaI, NO2, CN,5 COA, CHO, COOA, COOBenzyl, CONH2, CONHA,(CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S (O) m A, Hal, NO 2 , CN, 5 COA, CHO, COOA, COOBenzyl, CONH 2 , CONHA,
CONAA1, SO2NH2, (CH2)nNH2, (CH2)nNHA, (CH2)nNAA\ NHSO2A und/oder =0 (Carbonylsauerstoff) substituiertes Pyridyl, Pyrimidinyl, Furyl, Thienyl,Q Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Oxazolyl,CONAA 1 , SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) nNAA \ NHSO 2 A and / or = O (carbonyl oxygen) substituted pyridyl, pyrimidinyl, furyl, thienyl, Q Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl,
Isoxazolyl, Thiazolyl, Benzothiazolyl, Benzo[1 ,4]- dioxanyl, Chinolyl, Isochinolyl, Chinazolinyl, Benzimidazolyl, Indazolyl, Indolyl, 1 ,3-Dihydro- isoindolyl, Benzofuranyl, Dihydro-benzofuranyl,5Isoxazolyl, thiazolyl, benzothiazolyl, benzo [1,4] dioxanyl, quinolyl, isoquinolyl, quinazolinyl, benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzofuranyl, 5
Benzo[1 ,3]dioxolyl, Piperazinyl, Pyrazinyl, Pyridazinyl,Benzo [1,3] dioxolyl, piperazinyl, pyrazinyl, pyridazinyl,
Morpholinyl, Azepanyl, Pyrrolidinyl oder Piperidinyl, bedeutet, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Morpholinyl, azepanyl, pyrrolidinyl or piperidinyl, and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.
3. Verbindungen nach Anspruch 1 oder 2, worin3. Compounds according to claim 1 or 2, wherein
Het1 unsubstituiertes oder ein-, zwei- oder dreifach durch A, OA, OH, HaI, CN und/oder =O (Carbonylsauerstoff) substituiertes Pyridyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Benzimidazolyl, Triazolyl, Morpholinyl, Pyrimidinyl, Piperidinyl, Pyrrolidinyl oder Piperazinyl, bedeutet, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Het 1 pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, benzimidazolyl, triazolyl, morpholinyl, pyrimidinyl, piperidinyl, unsubstituted or mono-, di- or trisubstituted by A, OA, OH, Hal, CN and / or = O (carbonyl oxygen), Pyrrolidinyl or piperazinyl, as well as their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all proportions.
4. Verbindungen nach einem oder mehreren der Ansprüche 1-3, worin4. Compounds according to one or more of claims 1-3, wherein
A, A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-6 C-Atomen, worin 1-2 CH2- Gruppen durch O1 NH und/oder NMe und/oder auch 1- 5 H-Atome durch F, OH und/oder Cl ersetzt sein können, oder cyclisches Alkyl mit 3-8 C-Atomen, worin 1-3 H-Atome durch OH ersetzt sein können, bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate,A, A 'are each independently of one another unbranched or branched alkyl having 1-6 C atoms, in which 1-2 CH 2 - groups by O 1 NH and / or NMe and / or also 1-5 H-atoms by F, OH and or Cl may be substituted, or cyclic alkyl having 3-8 C atoms, in which 1-3 H atoms may be replaced by OH, and their pharmaceutically usable derivatives, salts, solvates,
Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Tautomers and stereoisomers, including mixtures thereof in all ratios.
5. Verbindungen nach einem oder mehreren der Ansprüche 1-4, worin n 0, 1 oder 2 bedeutet, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate,5. Compounds according to one or more of claims 1-4, wherein n is 0, 1 or 2, and their pharmaceutically usable derivatives, salts, solvates,
Tautomere und Stereoisomere, einschließlich deren Mischungen in 5 allen Verhältnissen.Tautomers and stereoisomers, including mixtures thereof in all ratios.
6. Verbindungen nach einem oder mehreren der Ansprüche 1-5, worin6. Compounds according to one or more of claims 1-5, wherein
R2 und R3 zusammen mit dem N-Atom an das sie gebunden 10 sind, auch unsubstituiertes oder ein-, zwei- oder dreifach durch HaI1 A, (CH2)nOH, (CH2)nOA und/oder =O (Carbonylsauerstoff) substituiertes 1 ,3-Dihydro- isoindolyl, Pyrrolidinyl, Azepanyl, Piperazinyl, ^ c Piperidinyl oder Morpholinyl, bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.R 2 and R 3 together with the N-atom to which they are attached are also unsubstituted or mono-, di- or trisubstituted by Hal 1 A, (CH 2 ) n OH, (CH 2 ) n OA and / or = O (carbonyl oxygen) substituted 1, 3-dihydro-isoindolyl, pyrrolidinyl, azepanyl, piperazinyl, ^ c piperidinyl or morpholinyl, and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.
2020
Verbindungen nach einem oder mehreren der Ansprüche 1-6, worinCompounds according to one or more of claims 1-6, wherein
R2 HH,, MMeetthhyyll,, EEtthhyyll,, 22--HHyyddrrooxxyyeetthhyyll,, 22--MMeethoxyethyl, 2- (Pyridin-2-ylamino)-ethyl oder Benzyl,R 2 HH ,, M-thethylyl, E-ththylyl ,, 22-H-hydroxydrxy-oxy-ethylthiophyl, 22-methoxyethyl, 2- (pyridin-2-ylamino) -ethyl or benzyl,
25 bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.25, and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.
3030
8. Verbindungen nach einem oder mehreren der Ansprüche 1-7, worin8. Compounds according to one or more of claims 1-7, wherein
R3 Methyl, Ethyl, Propyl, Butyl, Isopropyl, Phenyl,R 3 is methyl, ethyl, propyl, butyl, isopropyl, phenyl,
Benzyl, Furyl-2-ylmethyl, HC≡C-CH2-, 2-Methoxy- ethyl, 3-Trifluormethyl-benzyl, Pyridin-2- oder 3-Benzyl, furyl-2-ylmethyl, HC≡C-CH 2 -, 2-methoxy-ethyl, 3-trifluoromethyl-benzyl, pyridine-2 or 3
35 ylmethyl, 2-, 3- oder 4-Fluor-benzyl, 2-, 3- oder 4-35 ylmethyl, 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-
Methoxy-benzyl, 2-, 3- oder 4-Methylbenzyl, 3-Chlor- 6-methoxy-benzyl, N.N-Dimethylamino- carbonylmethyl, 4-([1 ,2,4]Triazol-1-ylmethyl)-benzyl, 2- oder 3-(Pyridin-3-yl)-benzyl, 3-(2-Morpholin-4-yl- ethoxy)-benzyl, 4-(Triazol-1-yl)-benzyl, 3-(Morpholin-Methoxybenzyl, 2-, 3- or 4-methylbenzyl, 3-chloro 6-methoxy-benzyl, N, N-dimethylaminocarbonylmethyl, 4 - ([1, 2,4] triazol-1-ylmethyl) -benzyl, 2- or 3- (pyridin-3-yl) -benzyl, 3- (2 Morpholin-4-ylethoxy) benzyl, 4- (triazol-1-yl) benzyl, 3- (morpholine)
4-yl)-benzyl, 3-(Pyrimidin-5-yl)-benzyl, 3-(Morpholin- 4-ylmethyl)-benzyl, Cyclopropylmethyl, 2-Cyanethyl, 2-Dimethylamino-ethyl, Cyclohexyl, 3- oder 4- (Methylsulfonylamino)-benzyl, 4-(Methylsulfonyl- aminomethyl)-benzyl, Benzo[1 ,4]dioxan-6-ylmethyl,4-yl) benzyl, 3- (pyrimidin-5-yl) benzyl, 3- (morpholin-4-ylmethyl) benzyl, cyclopropylmethyl, 2-cyanoethyl, 2-dimethylamino-ethyl, cyclohexyl, 3- or 4- (Methylsulfonylamino) benzyl, 4- (methylsulfonylaminomethyl) benzyl, benzo [1, 4] dioxan-6-ylmethyl,
Morpholin-4-yl, 2-Hydroxyethyl, 2-Methoxyethyl, 1 ,3,5-Trimethyl-i H-pyrazol-4-ylmethyl, 2-Methylsulfanil-ethyl, 2-Hydroxy-2-phenyl-ethyl, 2- (N-Ethyl-N-methyl-amino)-ethyl, 2-Diethylamino-ethyl,Morpholin-4-yl, 2-hydroxyethyl, 2-methoxyethyl, 1, 3,5-trimethyl-1H-pyrazol-4-ylmethyl, 2-methylsulfanil-ethyl, 2-hydroxy-2-phenylethyl, 2- N-ethyl-N-methylamino) -ethyl, 2-diethylamino-ethyl,
1-Methyl-1 H-pyrazol-3-yl, Chinolin-5- oder 8-yl, 2- Methylsulfanil-phenyl, Biphenyl-2-yl, 5,6,7,8- Tetrahydro-naphthalin-1-yl, 2-(1 H-Benzimidazol-2-yl)- phenyl, 3,4,5-Trimethoxy-phenyl, 2-Ethinylphenyl oder 1-Methyl-5-trifluormethyl-1 H-indazol-3-yl, bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.1-methyl-1H-pyrazol-3-yl, quinoline-5 or 8-yl, 2-methylsulfanil-phenyl, biphenyl-2-yl, 5,6,7,8-tetrahydro-naphthalen-1-yl, 2- (1H-benzimidazol-2-yl) -phenyl, 3,4,5-trimethoxyphenyl, 2-ethynylphenyl or 1-methyl-5-trifluoromethyl-1H-indazol-3-yl, and theirs pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios.
9. Verbindungen nach einem oder mehreren der Ansprüche 1-8, worin9. Compounds according to one or more of claims 1-8, wherein
R1 H, A, (CH2)nCONH2, (CH2)nCONHA, (CH2)OCONAA1, HaI, (CH2)nNH2, (CH2)nNHA, (CHz)nNAA1, CN, NO2,R 1 H, A, (CH 2 ) nCONH 2 , (CH 2 ) n CONHA, (CH 2 ) OCONAA 1 , Hal, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CHz) n NAA 1 , CN, NO 2 ,
(CH2)nAr, OAr, (CH2)nCOOH, (CH2)nCOOA, (CH2)nOH, (CH2)nOA, (CH2)nHet, COHet, C≡C-CH2SiA2A', C≡CH, C≡C-A, CH=CH-Ar1, CH=CH-COOA,(CH 2 ) n Ar, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het, COHet, C≡C-CH 2 SiA 2 A ', C≡CH, C≡CA, CH = CH-Ar 1 , CH = CH-COOA,
CH2CH(OH)CH2OH, O(CH2)nOH, NH(CH2)nOH,CH 2 CH (OH) CH 2 OH, O (CH 2 ) n OH, NH (CH 2 ) n OH,
O(CH2)nOA, NH(CH2)nOA, O(CH2)nNHA, NH(CH2)nNHA, NR4R5, (CH2)nCOOA, (CH2)nCONH(CH2)2CN, NH(CH2)nAr oder CH=CH-COOH,O (CH 2 ) n OA, NH (CH 2 ) n OA, O (CH 2 ) n NHA, NH (CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH (CH 2 ) 2 CN, NH (CH 2 ) n Ar or CH = CH-COOH,
R2 H1 A1 (CH2)nAr, (CH2)nHet, (CH2)nOH, (CH2)nOA,R 2 H 1 A 1 (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n OH, (CH 2 ) n OA,
(CH2)nNHHet, (CH2)nSA oder (CH2)nCH(OH)Ar, R3 A, (CH2)nAr, (CH2)nHet, (CH2)nCN, (CH2)nNH2,(CH 2 ) n NHHet, (CH 2 ) n SA or (CH 2 ) n CH (OH) Ar, R 3 A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n CN, (CH 2 ) n NH 2 ,
(CH2)nNHA, (CH2)HNAA1, (CH2)nOH, (CH2)nOA oder (CH2)nNHHet, R2 und R3 zusammen mit dem N-Atom an das sie gebunden sind, auch unsubstituiertes oder ein-, zwei- oder dreifach durch HaI, A, (CH2)nOH, (CH2)nOA und/oder =O (Carbonylsauerstoff) substituiertes 1 ,3-Dihydro- isoindolyl, Azepanyl, Pyrrolidinyl, Piperazinyl, Piperidinyl oder Morpholinyl,(CH 2 ) n NHA, (CH 2 ) H NAA 1 , (CH 2 ) n OH, (CH 2 ) n OA or (CH 2 ) n NHHet, R 2 and R 3 together with the N atom to which they also unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and / or = O (carbonyl oxygen) substituted 1,3-dihydro-isoindolyl, azepanyl, Pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl,
R4, R5 jeweils unabhängig voneinander (CH2)nOH, (CH2)nOA,R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
(CH2)nNH2, (CH2)nNHA oder (CH2JnNAA', Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI, (CH2)nOA, (CH2)nOH, (CH2)nCN, SA, SOA, SO2A1 NO2, C=CH, (CH2)nCOOH, CHO,(CH 2 ) n NH 2 , (CH 2 ) n NHA or (CH 2 J n NAA ', Ar unsubstituted or one, two, three, four or five times by A, Hal, (CH 2 ) n OA , (CH 2 ) n OH, (CH 2 ) n CN, SA, SOA, SO 2 A 1 NO 2 , C = CH, (CH 2 ) n COOH, CHO,
(CH2)nCOOA, CONH2, CONHA, CONAA', NHCOA, CH(OH)A, (CH2)nNH2, (CH2)nNHA, (CH2)nNAA', (CH2)nNAAr1, O(CH2)nHet1 , (CH2)nHet1, COO(CH2)nAr1 , (CH2)nNHSO2A, (CH2)nOAr1, O(CH2)nAr1,(CH 2 ) n COOA, CONH 2 , CONHA, CONAA ', NHCOA, CH (OH) A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA', (CH 2 ) n NAAr 1 , O (CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO (CH 2 ) n Ar 1 , (CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 , O (CH 2 ) n Ar 1 ,
SO2NH(CH2)nNH2, SO2NH2, SO2NHA, SO2NAA1, CONHAr1, CONH(CH2)nCOOA, CONH(CH2)nCOOH, NHCO(CH2)nCOOA, NHCO(CH2)nCOOH, CONH(CH2)nNH2, CONH(CH2)nNHA, CONH(CH2)nNAA',SO 2 NH (CH 2 ) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 , CONHAr 1 , CONH (CH 2 ) n COOA, CONH (CH 2 ) n COOH, NHCO (CH 2 ) n COOA, NHCO (CH 2 ) n COOH, CONH (CH 2 ) n NH 2 , CONH (CH 2 ) n NHA, CONH (CH 2 ) n NAA ',
CONH(CH2)nCN, NHCOHet, SO2Het, COHet und/oder (CH2)nCH(NH2)COOH substituiertes Phenyl, Naphthyl, Tetrahydronaphthyl oder Biphenyl,CONH (CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and / or (CH 2 ) n CH (NH 2 ) COOH substituted phenyl, naphthyl, tetrahydronaphthyl or biphenyl,
Ar1 unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI und/oder OA substituiertesAr 1 is unsubstituted or mono-, di-, tri-, tetra- or quintuply substituted by A, Hal and / or OA
Phenyl, Het unsubstituiertes oder ein-, zwei- oder dreifach durch A,phenyl, Het unsubstituted or one, two or three times by A,
(CH2)nOA, (CH2)nOH, Ar1, SH, S(O)1nA, HaI, NO2, CN, COA, CHO, COOA, COOBenzyl, CONH2, CONHA,(CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S (O) 1n A, Hal, NO 2 , CN, COA, CHO, COOA, COOBenzyl, CONH 2 , CONHA,
CONAA1, SO2NH2, (CH2)nNH2, (CH2)nNHA, (CH2)nNAA\ 5CONAA 1 , SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA \ 5
NHSO2A und/oder =0 (Carbonylsauerstoff) substituiertes Pyridyl, Pyrimidinyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Benzothiazolyl, Benzo[1 ,4]-NHSO 2 A and / or = 0 (carbonyl oxygen) substituted pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, benzo [1, 4] -
10 dioxanyl, Chinolyl, Isochinolyl, Chinazolinyl,10 dioxanyl, quinolyl, isoquinolyl, quinazolinyl,
Benzimidazolyl, Indazolyl, Indolyl, 1 ,3-Dihydro- isoindolyl, Benzofuranyl, Dihydro-benzofuranyl, Benzo[1 ,3]dioxolyl, Piperazinyl, Pyrazinyl, Pyridazinyl,Benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzofuranyl, benzo [1,3] dioxolyl, piperazinyl, pyrazinyl, pyridazinyl,
^ c Morpholinyl, Azepanyl, Pyrrolidinyl oder Piperidinyl, ^ C morpholinyl, azepanyl, pyrrolidinyl or piperidinyl,
Het1 unsubstituiertes oder ein-, zwei- oder dreifach durch A,Het 1 is unsubstituted or mono-, di- or trisubstituted by A,
OA, OH, HaI, CN und/oder =0 (Carbonylsauerstoff) substituiertes Pyridyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl,OA, OH, Hal, CN and / or = O (carbonyl oxygen) substituted pyridyl, furyl, thienyl, pyrrolyl, imidazolyl,
Benzimidazolyl, Triazolyl, Morpholinyl, Pyrimidinyl,Benzimidazolyl, triazolyl, morpholinyl, pyrimidinyl,
2020
Piperidinyl, Pyrrolidinyl oder Piperazinyl,Piperidinyl, pyrrolidinyl or piperazinyl,
A, A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-6 C-Atomen, worin 1-2 CH2- Gruppen durch O, NH und/oder NMe und/oder auch 1-5A, A 'are each independently of one another unbranched or branched alkyl having 1-6 C atoms, in which 1-2 CH 2 - groups by O, NH and / or NMe and / or also 1-5
25 H-Atome durch F, OH und/oder Cl ersetzt sein können, oder cyclisches Alkyl mit 3-8 C-Atomen, worin 1-3 H-Atome durch OH ersetzt sein können, 30 m O1 1 oder 2, n O, 1 oder 2, bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate,25 H atoms may be replaced by F, OH and / or Cl, or cyclic alkyl having 3-8 C atoms, wherein 1-3 H atoms may be replaced by OH, 3 0 m O 1 1 or 2, n O, 1 or 2, and their pharmaceutically usable derivatives, salts, solvates,
Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen. Tautomers and stereoisomers, including mixtures thereof in all ratios.
10. Verbindungen nach einem oder mehreren der Ansprüche 1-9, worin R1 H, A, (CHs)nCONH2, (CH2)nCONHA, (CH2JnCONAA1,10. Compounds according to one or more of claims 1-9, wherein R 1 is H, A, (CH 3) n CONH 2 , (CH 2 ) n CONHA, (CH 2 J n CONAA 1 ,
HaI, (CH2)nNH2, (CH2)nNHA, (CH2JnNAA1, CN, NO2, (CH2JnAr, OAr, (CH2JnCOOH, (CH2JnCOOA, (CH2JnOH, (CH2JnOA, (CH2)nHet, COHet, C≡C-CH2SiA2A\ C≡CH,Hal, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 J n NAA 1 , CN, NO 2 , (CH 2 J n Ar, OAr, (CH 2 J n COOH, (CH 2 J n COOA, (CH 2 J n OH, (CH 2 J n OA, (CH 2 ) n Het, COHet, C≡C-CH 2 SiA 2 A \ C≡CH,
C≡C-A, CH=CH-Ar1, CH=CH-COOA, CH2CH(OH)CH2OH, 0(CH2JnOH, NH(CH2)nOH, O(CH2)nOA, NH(CH2)nOA, O(CH2)nNHA, NH(CH2JnNHA,0 NR4R5, (CH2JnCOOA, (CH2JnCONH(CH2J2CN,C≡CA, CH = CH-Ar 1, CH = CH-COOA, CH 2 CH (OH) CH 2 OH, 0 (CH 2 J n OH, NH (CH 2) n OH, O (CH 2) n OA , NH (CH 2 ) n OA, O (CH 2 ) n NHA, NH (CH 2 J n NHA, O NR 4 R 5 , (CH 2 J n COOA, (CH 2 J n CONH (CH 2 J 2 CN .
NH(CH2JnAr oder CH=CH-COOH,NH (CH 2) n Ar or CH = CH-COOH,
R2 H, Methyl, Ethyl, 2-Hydroxyethyl, 2-Methoxyethyl, 2-R 2 is H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2
(Pyridin-2-ylamino)-ethyl oder Benzyl, 5 R3 Methyl, Ethyl, Propyl, Butyl, Isopropyl, Phenyl, Benzyl,(Pyridin-2-ylamino) ethyl or benzyl, 5 R 3 is methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl,
Furyl-2-ylmethyl, HC≡C-CH2-, 2-Methoxy-ethyl, 3- Trifluormethyl-benzyl, Pyridin-2- oder 3-ylmethyl, 2-, 3- oder 4-Fluor-benzyl, 2-, 3- oder 4-Methoxy-benzyl, 2-, 3- oder 4-Methylbenzyl, 3-Chlor-6-methoxy-benzyl, N1N-0Furyl-2-ylmethyl, HC≡C-CH 2 -, 2-methoxy-ethyl, 3-trifluoromethyl-benzyl, pyridin-2 or 3-ylmethyl, 2-, 3- or 4-fluoro-benzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-methylbenzyl, 3-chloro-6-methoxy-benzyl, N 1 N-O
Dimethylamino-carbonylmethyl, 4-([1 ,2,4]Triazol-1 - ylmethylj-benzyl, 2- oder 3-(Pyridin-3-yl)-benzyl, 3-(2- Morpholin-4-yl-ethoxy)-benzyl, 4-(Triazol-1-yl)-benzyl, 3- (Morpholin-4-yl)-benzyl, 3-(Pyrimidin-5-yl)-benzyl, 3-5 (Morpholin-4-ylmethyl)-benzyl, Cyclopropylmethyl, 2-Dimethylamino-carbonylmethyl, 4 - ([1, 2,4] triazol-1-ylmethyl-benzyl, 2- or 3- (pyridin-3-yl) -benzyl, 3- (2-morpholin-4-yl-ethoxy) benzyl, 4- (triazol-1-yl) benzyl, 3- (morpholin-4-yl) benzyl, 3- (pyrimidin-5-yl) benzyl, 3-5 (morpholin-4-ylmethyl) - benzyl, cyclopropylmethyl, 2-
Cyanethyl, 2-Dimethylamino-ethyl, Cyclohexyl, 3- oder 4-(Methylsulfonylamino)-benzyl, 4-(Methylsulfonylamino- methylj-benzyl, Benzo[1 ,4]dioxan-6-ylmethyl, Morpholin-Q 4-yl, 2-Hydroxyethyl, 2-Methoxyethyl, 1 ,3,5-Trimethyl-Cyanoethyl, 2-dimethylamino-ethyl, cyclohexyl, 3- or 4- (methylsulfonylamino) benzyl, 4- (methylsulfonylamino methylj-benzyl, benzo [1, 4] dioxan-6-ylmethyl, morpholine Q 4-yl, 2 -Hydroxyethyl, 2-methoxyethyl, 1, 3,5-trimethyl
1 H-pyrazol-4-ylmethyl, 2-Methylsulfanil-ethyl, 2- Hydroxy-2-phenyl-ethyl, 2-(N-Ethyl-N-methyl-aminoJ- ethyl, 2-Diethylamino-ethyl, 1-Methyl-1 H-pyrazol-3-yl, Chinolin-5- oder 8-yl, 2-Methylsulfanil-phenyl, Biphenyl-5 2-yl, 5,6,7,8-Tetrahydro-naphthalin-1-yl, 2-(1 H-1 H-pyrazol-4-ylmethyl, 2-methylsulfanil-ethyl, 2-hydroxy-2-phenyl-ethyl, 2- (N-ethyl-N-methyl-amino-ethyl, 2-diethylamino-ethyl, 1-methyl- 1 H -pyrazol-3-yl, quinoline-5 or 8-yl, 2-methylsulfanil-phenyl, biphenyl- 5 2-yl, 5,6,7,8-tetrahydro-naphthalen-1-yl, 2- 1 H
Benzimidazol-2-yl)-phenyl, 3,4,5-Trimethoxy-phenyl, 2- Ethinylphenyl oder 1-Methyl-5-trifluormethyl-1 H-indazol-Benzimidazol-2-yl) -phenyl, 3,4,5-trimethoxyphenyl, 2- Ethynylphenyl or 1-methyl-5-trifluoromethyl-1H-indazole
3-yl, R2 und R3 zusammen mit dem N-Atom an das sie gebunden sind, auch unsubstituiertes oder ein-, zwei- oder dreifach durch HaI1 A1 (CH2)nOH, (CH2)nOA und/oder =O3-yl, R 2 and R 3 together with the N-atom to which they are attached, also unsubstituted or mono-, di- or trisubstituted by Hal 1 A 1 (CH 2 ) n OH, (CH 2 ) n OA and / or = O
(Carbonylsauerstoff) substituiertes 1 ,3-Dihydro- isoindolyl, Azepanyl, Pyrrolidinyl, Piperazinyl, Piperidinyl oder Morpholinyl, R4, R5 jeweils unabhängig voneinander (CH2)nOH, (CH2)nOA,(Carbonyl oxygen) substituted 1,3-dihydroisoindolyl, azepanyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl, R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
(CHz)nNH2, (CH2)nNHA oder (CH2)nNAA\ Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI, (CH2)nOA, (CH2)nOH, (CH2)nCN, SA, SOA, SO2A, NO2, C≡CH, (CH2)nCOOH, CHO,(CHz) n NH 2 , (CH 2 ) n NHA or (CH 2 ) n NAA \ Ar unsubstituted or one, two, three, four or five times by A, Hal, (CH 2 ) n OA, ( CH 2 ) n OH, (CH 2 ) n CN, SA, SOA, SO 2 A, NO 2 , C≡CH, (CH 2 ) n COOH, CHO,
(CH2)nCOOA, CONH2, CONHA, CONAA1, NHCOA,(CH 2 ) n COOA, CONH 2 , CONHA, CONAA 1 , NHCOA,
CH(OH)A, (CH2)nNH2, (CH2)nNHA, (CH2)nNAA', - (CH2)nNAAr1, O(CH2)nHet1, (CH2)nHet1, COO(CH2)nAr1,CH (OH) A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA ', - (CH 2 ) n NAAr 1 , O (CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO (CH 2 ) n Ar 1 ,
(CH2)nNHSO2A, (CH2)nOAr1, 0(CH2JnAr1,(CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 , 0 (CH 2 J n Ar 1 ,
SO2NH(CH2)nNH2, SO2NH2, SO2NHA, SO2NAA1,SO 2 NH (CH 2 ) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 ,
CONHAr1, CONH(CH2)nCOOA, CONH(CH2)nCOOH,CONHAr 1 , CONH (CH 2 ) n COOA, CONH (CH 2 ) n COOH,
NHCO(CH2)nCOOA, NHCO(CH2)nCOOH,NHCO (CH 2 ) n COOA, NHCO (CH 2 ) n COOH,
CONH(CH2)nNH2l CONH(CH2)nNHA, CONH(CH2)nNAA1, CONH(CH2)nCN, NHCOHet, SO2Het, COHet und/oderCONH (CH 2 ) n NH 2l CONH (CH 2 ) n NHA, CONH (CH 2 ) n NAA 1 , CONH (CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and / or
(CHz)nCH(NH2)COOH substituiertes Phenyl, Naphthyl,(CHz) n CH (NH 2 ) COOH substituted phenyl, naphthyl,
Tetrahydronaphthyl oder Biphenyl,Tetrahydronaphthyl or biphenyl,
Ar1 unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI und/oder OA substituiertesAr 1 is unsubstituted or mono-, di-, tri-, tetra- or quintuply substituted by A, Hal and / or OA
Phenyl, Het unsubstituiertes oder ein-, zwei- oder dreifach durchPhenyl, Het unsubstituted or mono-, di- or trisubstituted
HaI, Phenyl, A, (CH2)nOH, (CH2)nOA, COOH, COOA,Hal, phenyl, A, (CH 2 ) n OH, (CH 2 ) n OA, COOH, COOA,
COOBenzyl, CN, COA, CHO, (CH2)nNH2, (CH2)nNHA,COOBenzyl, CN, COA, CHO, (CH 2 ) n NH 2 , (CH 2 ) n NHA,
(CH2JnNAA1 und/oder =0 (Carbonylsauerstoff) substituiertes Pyridyl, Pyrimidinyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Benzothiazolyl, Benzo[1 ,4]- dioxanyl, Chinolyl, Isochinolyl, Chinazolinyl, Benzimidazolyl, Indazolyl, Indolyl, 1 ,3-Dihydro- isoindolyl, Benzofuranyl, Dihydro-benzofuranyl, Benzo[1 ,3]dioxolyl, Piperazinyl, Pyrazinyl, Pyridazinyl, Morpholinyl, Azepanyl, Pyrrolidinyl oder Piperidinyl,(CH 2 J n NAA 1 and / or = O (carbonyl oxygen) substituted pyridyl, pyrimidinyl, furyl, thienyl, Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, benzo [1,4] dioxanyl, quinolyl, isoquinolyl, quinazolinyl, benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzofuranyl , Benzo [1,3] dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, pyrrolidinyl or piperidinyl,
Het1 unsubstituiertes oder einfach durch =OHet 1 unsubstituted or simply by = O
(Carbonylsauerstoff) substituiertes Morpholinyl, Piperidinyl oder Pyrrolidinyl,(Carbonyl oxygen) substituted morpholinyl, piperidinyl or pyrrolidinyl,
A, A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-6 C-Atomen, worin 1-2 CH2- Gruppen durch O, NH und/oder NMe und/oder auch 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können, oder cyclisches Alkyl mit 3-8 C-Atomen, worin 1-3 H-Atome durch OH ersetzt sein können, m 0, 1 oder 2, n 0, 1 oder 2, bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate,A, A 'each independently of one another are unbranched or branched alkyl having 1-6 C atoms, in which 1-2 CH 2 - groups by O, NH and / or NMe and / or 1-5 H atoms by F, OH and or Cl may be substituted, or cyclic alkyl having 3-8 C atoms, wherein 1-3 H atoms may be replaced by OH, m is 0, 1 or 2, n is 0, 1 or 2, and their pharmaceutically usable derivatives, salts, solvates,
Tautomere und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Tautomers and stereoisomers, including mixtures thereof in all ratios.
11. Verbindungen nach Anspruch 1 ausgewählt aus der Gruppe11. Compounds according to claim 1 selected from the group
sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including mixtures thereof in all ratios.
12. Verfahren zur Herstellung von Verbindungen der Formel I nach den Ansprüchen 1-11 sowie ihrer pharmazeutisch verwendbaren12. A process for the preparation of compounds of the formula I according to claims 1-11 and their pharmaceutically acceptable
Derivate, Solvate, Salze und Stereoisomere, dadurch gekennzeichnet, daß manDerivatives, solvates, salts and stereoisomers, characterized in that
a) eine Verbindung der Formel Ila) a compound of formula II
worin wherein
R1 die in Anspruch 1 angegebene Bedeutung hat, und L F, Cl, Br, I oder eine freie oder eine reaktionsfähig abgewandelte OH-Gruppe bedeutet,R 1 has the meaning given in claim 1, and LF, Cl, Br, I or a free or a reactively modified OH group,
mit einer Verbindung der Formelwith a compound of the formula
NHR2R3 woπnNHR 2 R 3 embedded image in which
R2 und R3 die in Anspruch 1 angegebenen Bedeutungen haben,R 2 and R 3 have the meanings given in claim 1,
umsetzt,implements,
oderor
b) eine Verbindung der Formel IVb) a compound of formula IV
worin R1 , R2 und R3 die in Anspruch 1 angegebenen wherein R 1 , R 2 and R 3 are as defined in claim 1
Bedeutungen haben,Have meanings
mit einem 1 ,3-Bis(trialkylsilyl)carbodiimid umsetzt,with a 1, 3-bis (trialkylsilyl) carbodiimide,
oderor
c) in einer Verbindung der Formel I einen Rest R1 in einen anderen Rest R1 umwandelt, indem manc) in a compound of the formula I converts a radical R 1 into another radical R 1 by
i) eine Nitrogruppe zu einer Aminogruppe reduziert, ii) eine Estergruppe zu einer Carboxygruppe hydrolysiert, iii) eine Aldehydgruppe durch reduktive Aminierung in ein alkyliertes Amin umwandelt, iv) eine Carboxygruppe in eine Sulfonamidocarbonylgruppe umwandelt, v) ein Säurechlorid in ein Amid überführt, vi) ein Halogenatom gegen einen Aryl- oder Alkylrest austauscht, vii) eine Doppelbindung hydriert, viii) einen Ether spaltet, 0 jx) ein Halogenatom durch einen Arylrest ersetzt (Suzuki-i) reducing a nitro group to an amino group, ii) hydrolyzing an ester group to a carboxy group, iii) converting an aldehyde group to an alkylated amine by reductive amination, iv) converting a carboxy group to a sulfonamidocarbonyl group, v) converting an acid chloride to an amide, vi) exchanging a halogen atom for an aryl or alkyl radical, vii) hydrogenating a double bond, viii ) splits an ether, 0 jx) replaces a halogen atom with an aryl radical (Suzuki
Kopplung), x) ein Halogenatom durch eine Alkylamino-, Arylamino-,X) a halogen atom by an alkylamino, arylamino,
Alkoxy- oder eine Aryloxygruppe ersetzt, 5 und/oder eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.Replaced alkoxy or an aryloxy group, 5 and / or a base or acid of formula I converts into one of its salts.
13. Arzneimittel, enthaltend mindestens eine Verbindung nach AnspruchQ 1-11 und/oder ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.13. Medicaments containing at least one compound according to claim Q 1-11 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
14. Verwendung von Verbindungen gemäß Anspruch 1-1 1 , sowie ihrer5 pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von Krankheiten, bei denen die Hemmung, Regulierung und/oder14. Use of compounds according to claim 1-1 1, and their5 pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, for the preparation of a medicament for the treatment and / or prophylaxis of diseases in which the inhibition, regulation and / or
Modulation von HSP90 eine Rolle spielt. 0Modulation of HSP90 plays a role. 0
15. Verwendung nach Anspruch 14 von Verbindungen gemäß Anspruch 1-11 , sowie ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen 5 Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung oder Vorbeugung von Tumorerkrankungen, viralen Erkrankungen, zur Immunsuppression bei Transplantationen, entzündungsbedingten Erkrankungen, Zystische Fibrose, Erkrankungen im Zusammenhang mit Angiogenese, infektiösen Erkrankungen, Autoimmunerkrankun- gen, Ischämie, fibrogenetischen Erkrankungen, zur Förderung der Nervenregeneration, zur Hemmung des Wachstums von Krebs, Tumorzellen und Tumormetastasen, zum Schutz normaler Zellen gegen Toxizität, die durch Chemotherapie verursacht ist, zur Behandlung von Krankheiten, wobei Proteinfehlfaltung oder Aggregation ein Hauptkausalfaktor ist.15. Use according to claim 14 of compounds according to claim 1-11, and their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment or preventing tumor diseases, viral diseases, immunosuppression in transplantation, inflammatory diseases, cystic fibrosis, angiogenesis-related diseases, infectious diseases, autoimmune diseases, ischemia, fibrogenetic diseases, for promoting nerve regeneration, inhibiting the growth of cancer, tumor cells and tumor metastases, for protecting normal cells against toxicity caused by chemotherapy for the treatment of diseases, wherein protein misfolding or aggregation is a major causative factor.
16. Verwendung nach Anspruch 15, wobei es sich bei den Tumorerkrankungen um Fibrosarkom, Myxosarkom, Liposarkom, Chondrosarkom, osteogenem Sarkom, Chordom, Angiosarkom,16. Use according to claim 15, wherein the tumors are fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,
Endotheliosarkom, Lymphangiosarkom, Lymphangioendothelio- sarkom, Synoviom, Mesotheliom, Ewing-Tumor, Leiosarkom,Endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiosarcoma,
Rhabdomyosarkom, Kolonkarzinom, Pankreaskrebs, Brustkrebs, Ovarkrebs, Prostatakrebs, Plattenzellkarzinom, Basalzellkarzinom, Adenokarzinom, Schweißdrüsenkarzinom, Talgdrüsenkarzinom, Papillenkarzinom, Papillaradenokarzinomen, Cystadenokarzinomen,Rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma,
Knochenmarkkarzinom, bronchogenem Karzinom, Nierenzell- karzinom, Hepatom, Gallengangkarzinom, Chorionkarzinom, Seminom, embryonalem Karzinom, Wilms -Tumor, Cervix-Krebs, Hodentumor, Lungenkarzinom, kleinzelligem Lungenkarzinom,Bone marrow carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonic carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma,
Blasenkarzinom, Epithelkarzinom, Gliom, Astrocytom, Medulloblastom, Kraniopharyngiom, Ependymom, Pinealom, Hämangioblastom, akustischem Neurom, Oligodendrogliom,Bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma,
Meningiom, Melanom, Neuroblastom, Retinoblastom, Leukämie,Meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia,
Lymphom, multiplem Myelom, Waldenströms Makroglobulinämie undLymphoma, multiple myeloma, Waldenstrom's macroglobulinemia and
Schwere-Kettenerkrankung handelt. Heavy chain disease is.
17. Verwendung nach Anspruch 15, wobei das virale Pathogen der viralen Erkrankungen ausgewählt ist aus der Gruppe, bestehend aus Hepatitis Typ A, Hepatitis Typ B1 Hepatitis Typ C, Influenza, Varicella, Adenovirus, Herpes-Simplex Typ I (HSV-I)1 Herpes Simplex Typ Il (HSV-II), Rinderpest, Rhinovirus, Echovirus, Rotavirus, respiratorischem Synzytialvirus (RSV), Papillomvirus, Papovavirus, Cytomegalievirus, Echinovirus, Arbovirus, Huntavirus, Coxsackievirus, Mumpsvirus, Masernvirus, Röteinvirus, Poliovirus, menschliches Immunschwächevirus Typ I (HIV-I) und menschliches Immunschwächevirus Typ Il (HIV-II).17. Use according to claim 15, wherein the viral pathogen of the viral diseases is selected from the group consisting of hepatitis type A, hepatitis type B 1 type C hepatitis, influenza, varicella, adenovirus, herpes simplex type I (HSV-I). 1 Herpes simplex type II (HSV-II), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV), papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackievirus, mumpsvirus, measles virus, rotten virus, poliovirus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II).
18. Verwendung nach Anspruch 15, wobei es sich bei den entzündungsbedingten Erkrankungen um Rheumatoide Arthritis, Sepsis, Asthma, Multiple Sklerose, Typ 1 Diabetes, Lupus Erythematodes, Psoriasis und Inflammatory Bowel Disease handelt.18. Use according to claim 15, wherein the inflammatory diseases are rheumatoid arthritis, sepsis, asthma, multiple sclerosis, type 1 diabetes, lupus erythematosus, psoriasis and inflammatory bowel disease.
19. Verwendung nach Anspruch 15, wobei es sich bei den Erkrankungen im Zusammenhang mit Angiogenese um diabetische Retinopathie, Hämangiome, Endometriose und Tumorangiogenese handelt.Use according to claim 15, wherein the diseases associated with angiogenesis are diabetic retinopathy, hemangiomas, endometriosis and tumor angiogenesis.
20. Verwendung nach Anspruch 15, wobei es sich bei den fibrogenetischen Erkrankungen um Sklerodermie, Polymyositis, systemischer Lupus, Leberzirrhose, Keloidbildung, interstitielle Nephritis und pulmonare Fibrose handelt.Use according to claim 15, wherein said fibrogenetic disorders are scleroderma, polymyositis, systemic lupus, cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.
21. Verwendung nach Anspruch 15, wobei es sich bei den Krankheiten, bei denen Proteinfehlfaltung oder Aggregation ein Hauptkausalfaktor ist, um Skrapie, Creutzfeldt-Jakob-Krankheit, Huntington oderUse according to claim 15, wherein the diseases in which protein misfolding or aggregation is a major causative factor are scrapie, Creutzfeldt-Jakob disease, Huntington's or
Alzheimer handelt. Alzheimer's is acting.
22. Arzneimittel enthaltend mindestens eine Verbindung gemäß Anspruch 1-11 und/oder ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und mindestens einen weiteren Arzneimittelwirkstoff.22. Medicaments containing at least one compound according to claim 1-11 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, and at least one further active pharmaceutical ingredient.
23. Set (Kit), bestehend aus getrennten Packungen von23. Set (Kit) consisting of separate packs of
(a) einer wirksamen Menge an einer Verbindung gemäß Anspruch 1-11 und/oder ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und(A) an effective amount of a compound according to claim 1-11 and / or their pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and
(b) einer wirksamen Menge eines weiteren Arzneimittelswirkstoffs.(b) an effective amount of another drug active.
24. Verbindungen der Formel IV24. Compounds of the formula IV
worin R1 H, A, (CH2)nCONH2, (CH2)nCONHA, (CH2)nCONAA\ HaI, (CHa)nNH2, (CH2)nNHA, (CH2JnNAA1, CN1 NO2, (CH2JnAr, OAr1 (CH2)nCOOH, (CH2)nCOOA, (CH2)nOH, (CH2)nOA, (CH2)nHet, COHet, C=C-CH2SiA2A1, C≡CH, C≡C-A, CH=CH-Ar1, CH=CH-COOA, CH2CH(OH)CH2OH1 O(CH2)nOH, NH(CH2)nOH, O(CH2)nOA, NH(CH2)nOA, O(CH2)nNHA, NH(CH2)nNHA, NR4R5, (CH2)nCOOA, (CH2)nCONH(CH2)2CN, NH(CH2)nAr oder CH=CH-COOH, R2 H1 A, (CH2)nAr, (CH2)nHet, (CH2)nOH, (CH2)nOA, (CH2)nNHHet, (CH2)nSA oder (CH2)nCH(OH)Ar, wherein R 1 is H, A, (CH 2 ) n CONH 2, (CH 2 ) n CONHA, (CH 2 ) n CONAA \ Hal, (CHa) n NH 2 , (CH 2 ) n NHA, (CH 2 J n NAA 1 , CN 1 NO 2 , (CH 2 J n Ar, OAr 1 (CH 2 ) n COOH, (CH 2 ) n COOA, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het , COHet, C =C-CH 2 SiA 2 A 1 , C≡CH, C≡CA, CH =CH-Ar 1 , CH =CH-COOA, CH 2 CH (OH) CH 2 OH 1 O (CH 2 ) n is OH, NH (CH 2 ) n OH, O (CH 2 ) n OA, NH (CH 2 ) n OA, O (CH 2 ) n NHA, NH (CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH (CH 2 ) 2 CN, NH (CH 2 ) n Ar or CH = CH-COOH, R 2 H 1 A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NHHet, (CH 2 ) n SA or (CH 2 ) n CH (OH) Ar,
R3 A, (CH2)nAr, (CH2)nHet, (CH2)nCN, (CH2)nNH2,R 3 A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n CN, (CH 2 ) n NH 2 ,
(CH2)nNHA, (CH2)nNAA1, (CH2)nOH, (CH2)nOA oder (CH2)nNHHet, R2 und R3 zusammen mit dem N-Atom an das sie gebunden sind, auch einen unsubstituierten oder ein-, zwei- oder dreifach durch HaI, A, (CH2)nOH, (CH2)nOA und/oder =O (Carbonylsauerstoff) substituierten gesättigten, ungesättigten oder aromatischen mono- oder bicyclischen Heterocyclus, der weitere 1 bis 3 N-, O- und/oder S-Atome enthalten kann,(CH 2 ) n NHA, (CH 2 ) nNAA 1 , (CH 2 ) n OH, (CH 2 ) n OA or (CH 2 ) n NHHet, R 2 and R 3 together with the N atom to which they are attached are also an unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and / or = O (carbonyl oxygen) substituted, saturated, unsaturated or aromatic mono- or bicyclic heterocycle which may contain an additional 1 to 3 N, O and / or S atoms,
R4, R5 jeweils unabhängig voneinander (CH2)nOH, (CH2)nOA,R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
(CH2)nNH2, (CH2)nNHA oder (CH2JnNAA1, Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI, (CH2JnOA, (CH2JnOH, (CH2JnCN, SA, SOA, SO2A1 NO2, C≡CH, (CH2JnCOOH1 CHO, (CH2JnCOOA, CONH2, CONHA, CONAA1, NHCOA, CH(OH)A1 (CH2JnNH2, (CH2JnNHA1 (CH2JnNAA1,(CH 2 ) n NH 2 , (CH 2 ) n NHA or (CH 2 J n NAA 1 , Ar unsubstituted or one, two, three, four or five times by A, Hal, (CH 2 J n OA , (CH2 J n OH, (CH 2 J n CN, SA, SOA, SO 2 A 1 NO 2, C≡CH, (CH 2 J n COOH 1 CHO, (CH 2 J n COOA, CONH 2, CONHA , CONAA 1 , NHCOA, CH (OH) A 1 (CH 2 J n NH 2 , (CH 2 J n NHA 1 (CH 2 J n NAA 1 ,
(CH2JnNAAr1, O(CH2)nHet1, (CH2)nHet1 , COO(CH2JnAr1, (CH2JnNHSO2A, (CH2JnOAr1, 0(CH2JnAr1, SO2NH(CH2JnNH2, SO2NH2, SO2NHA, SO2NAA1, CONHAr1, CONH(CH2JnCOOA1 CONH(CH2JnCOOH,(CH 2 J n NAAr 1 , O (CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO (CH 2 J n Ar 1 , (CH 2 J n NHSO 2 A, (CH 2 J n OAr 1 , 0 (CH 2 J n Ar 1 , SO 2 NH (CH 2 J n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 , CONHAr 1 , CONH (CH 2 J n COOA 1 CONH (CH 2 J n COOH,
NHCO(CH2JnCOOA, NHCO(CH2JnCOOH1 CONH(CH2JnNH2, CONH(CH2JnNHA, CONH(CH2JnNAA1, CONH(CH2JnCN1 NHCOHet, SO2Het, COHet und/oderNHCO (CH 2 J n COOA, NHCO (CH 2 J n COOH 1 CONH (CH 2 J n NH 2 , CONH (CH 2 J n NHA, CONH (CH 2 J n NAA 1 , CONH (CH 2 J n CN 1 NHCOHet, SO 2 Het, COHet and / or
(CH2JnCH(NH2)COOH substituiertes Phenyl, Naphthyl,(CH 2 J n CH (NH 2 ) COOH substituted phenyl, naphthyl,
Tetrahydronaphthyl oder Biphenyl, Ar1 unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI und/oder OA substituiertes Phenyl,Tetrahydronaphthyl or biphenyl, Ar 1 is unsubstituted or mono-, di-, tri-, tetra- or quintuple phenyl substituted by A, Hal and / or OA,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch A, (CH2)nOA, (CH2)nOH, Ar1, SH, S(OJmA1 HaI, NO2, CN, COA, CHO, COOA, COOBenzyl, CONH2, CONHA, CONAA1, SO2NH2, (CH2JnNH2,Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S (OJmA 1 Hal, NO 2 , CN, COA, CHO, COOA, COOBenzyl, CONH 2 , CONHA, CONAA 1 , SO 2 NH 2 , (CH 2 J n NH 2 ,
(CH2JnNHA, (CH2JnNAA1, NHSO2A und/oder =O (Carbonylsauerstoff) substituiert sein kann, Het1 einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der unsubstituiert oder ein- oder zweifach durch A, OA, OH, HaI, CN und/oder =0 (Carbonylsauerstoff) substituiert sein kann,(CH 2 J n NHA, (CH 2 J n NAA 1 , NHSO 2 A and / or = O (carbonyl oxygen) may be substituted, Het 1 is a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N-, O and / or S atoms which may be unsubstituted or mono- or disubstituted by A, OA, OH, Hal, CN and / or 0O (carbonyl oxygen),
A, A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-10 C-Atomen, worin 1-3 nicht- benachbarte CH2-Gruppen durch O, S, SO, SO2, NH, NMe oder NEt und/oder auch 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können, Alk1, cyclisches Alkyl mit 3-8 C-Atomen oderA, A 'are each independently of one another unbranched or branched alkyl having 1-10 C atoms, in which 1-3 non-adjacent CH 2 groups are represented by O, S, SO, SO 2 , NH, NMe or NEt and / or 1 -5 H atoms can be replaced by F, OH and / or Cl, Alk 1 , cyclic alkyl having 3-8 C atoms or
Cycloalkylalkylen, worin 1-5 H-Atome durch F, OH und/oder Cl ersetzt sein können, Alk1 Alkenyl oder Alkinyl mit 2-6 C-Atomen, m O, 1 oder 2, n O, 1 , 2, 3 oder 4, bedeuten, sowie deren Salze.Cycloalkylalkylen, wherein 1-5 H-atoms can be replaced by F, OH and / or Cl, Alk 1 alkenyl or alkynyl with 2-6 C-atoms, m O, 1 or 2, n O, 1, 2, 3 or 4, and their salts.
25. Verbindungen nach Anspruch 24, worin R1 H1 A1 (CH2)nCONH2l (CH2)nCONHA, (CH2)OCONAA1,25. Compounds according to claim 24, wherein R 1 H 1 A 1 (CH 2 ) n CONH 2 l (CH 2 ) n CONHA, (CH 2 ) O CONAA 1 ,
HaI1 (CH2)nNH2l (CH2JnNHA1 (CH2JnNAA1, CN, NO2, (CH2)nAr, OAr, (CH2)nCOOH, (CH2)nCOOA, (CH2)nOH, (CH2)nOA, (CH2)nHet, COHet, CEC-CH2SiA2A1, C≡CH, C≡C-A, CH=CH-Ar1 , CH=CH-COOA,Hal 1 (CH 2 ) n NH 2 l (CH 2 J n NHA 1 (CH 2 J n NAA 1 , CN, NO 2 , (CH 2 ) n Ar, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het, COHet, CEC-CH 2 SiA 2 A 1 , C≡CH, C≡CA, CH = CH-Ar 1 , CH = CH-COOA,
CH2CH(OH)CH2OH1 O(CH2)nOH, NH(CH2)nOH, O(CH2)nOA, NH(CH2)nOA, O(CH2)nNHA, NH(CH2)nNHA, NR4R5, (CH2)nCOOA, (CH2)nCONH(CH2)2CN, NH(CH2)nAr oder CH=CH-COOH,CH 2 CH (OH) CH 2 OH 1 O (CH 2 ) n OH, NH (CH 2 ) n OH, O (CH 2 ) n OA, NH (CH 2 ) n OA, O (CH 2 ) n NHA, NH (CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH (CH 2 ) 2 CN, NH (CH 2 ) n Ar or CH = CH-COOH,
R2 H, Methyl, Ethyl, 2-Hydroxyethyl, 2-Methoxyethyl, 2-R 2 is H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2
(Pyridin-2-ylamino)-ethyl oder Benzyl, R3 Methyl, Ethyl, Propyl, Butyl, Isopropyl, Phenyl, Benzyl, Furyl-2-ylmethyl, HC≡C-CH2-, 2-Methoxy-ethyl, 3-(Pyridin-2-ylamino) -ethyl or benzyl, R 3 is methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl, furyl-2-ylmethyl, HC≡C-CH 2 -, 2-methoxy-ethyl, 3
Trifluormethyl-benzyl, Pyridin-2- oder 3-ylmethyl, 2-, 3- oder 4-Fluor-benzyl, 2-, 3- oder 4-Methoxy-benzyl, 2-, 3- oder 4-Methylbenzyl, 3-Chlor-6-methoxy-benzyl, N1N-Trifluoromethylbenzyl, pyridin-2 or 3-ylmethyl, 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-methylbenzyl, 3-chloro 6-methoxybenzyl, N 1 N-
Dimethylamino-carbonylmethyl, 4-([1 ,2,4]Triazol-1- ylmethyl)-benzyl, 2- oder 3-(Pyridin-3-yl)-benzyl, 3-(2-Dimethylamino-carbonylmethyl, 4 - ([1, 2,4] triazol-1-ylmethyl) benzyl, 2- or 3- (pyridin-3-yl) benzyl, 3- (2-
Morpholin-4-yl-ethoxy)-benzyl, 4-(Triazol-1-yl)-benzyl, 3- (Morpholin-4-yl)-benzyl, 3-(Pyrimidin-5-yl)-benzyl, 3- (Morpholin-4-ylmethyl)-benzyl, Cyclopropylmethyl, 2- Cyanethyl, 2-Dimethylamino-ethyl, Cyclohexyl, 3- oderMorpholin-4-yl-ethoxy) -benzyl, 4- (triazol-1-yl) -benzyl, 3- (morpholin-4-yl) -benzyl, 3- (pyrimidin-5-yl) -benzyl, 3- ( Morpholin-4-ylmethyl) benzyl, cyclopropylmethyl, 2-cyanoethyl, 2-dimethylamino-ethyl, cyclohexyl, 3-or
4-(Methylsulfonylamino)-benzyl, 4-(Methylsulfonylamino- methyl)-benzyl, Benzo[1 ,4]dioxan-6-ylmethyl, Morpholin- 4-yl, 2-Hydroxyethyl, 2-Methoxyethyl, 1 ,3,5-Trimethyl- 1 H-pyrazol-4-ylmethyl, 2-Methylsulfanil-ethyl, 2-4- (methylsulfonylamino) -benzyl, 4- (methylsulfonylamino-methyl) -benzyl, benzo [1,4] dioxan-6-ylmethyl, morpholin-4-yl, 2-hydroxyethyl, 2-methoxyethyl, 1, 3,5- Trimethyl-1H-pyrazol-4-ylmethyl, 2-methylsulfanil-ethyl, 2-
Hydroxy-2-phenyl-ethyl, 2-(N-Ethyl-N-methyl-amino)- ethyl, 2-Diethylamino-ethyl, 1-Methyl-1 H-pyrazol-3-yl, Chinolin-5- oder 8-yl, 2-Methylsulfanil-phenyl, Biphenyl-Hydroxy-2-phenyl-ethyl, 2- (N-ethyl-N-methylamino) ethyl, 2-diethylamino-ethyl, 1-methyl-1H-pyrazol-3-yl, quinoline-5 or 8- yl, 2-methylsulfanil-phenyl, biphenyl
2-yl, 5,6,7,8-Tetrahydro-naphthalin-i-yl, 2-(1 H-2-yl, 5,6,7,8-tetrahydronaphthalene-i-yl, 2- (1H-
Benzimidazol-2-yl)-phenyl, 3,4,5-Trimethoxy-phenyl, 2- Ethinylphenyl oder 1-Methyl-5-trifluormethyl-1 H-indazol-Benzimidazol-2-yl) -phenyl, 3,4,5-trimethoxyphenyl, 2- Ethynylphenyl or 1-methyl-5-trifluoromethyl-1H-indazole
3-yl, R2 und R3 zusammen mit dem N-Atom an das sie gebunden sind, auch unsubstituiertes oder ein-, zwei- oder dreifach 5 durch HaI1 A, (CH2)nOH, (CH2)nOA und/oder =03-yl, R 2 and R 3 to which they are together with the N-atom attached may also form unsubstituted or mono-, di- or trisubstituted by Hal 1 5 A, (CH 2) n OH, (CH 2) n OA and / or = 0
(Carbonylsauerstoff) substituiertes 1 ,3-Dihydro- isoindolyl, Azepanyl, Pyrrolidinyl, Piperazinyl, Piperidinyl oder Morpholinyl, 10 R4, R5 jeweils unabhängig voneinander (CH2)nOH, (CH2)nOA,(Carbonyl oxygen) substituted 1,3-dihydroisoindolyl, azepanyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl, 10 R 4 , R 5 are each independently (CH 2 ) n OH, (CH 2 ) n OA,
(CH2)nNH2, (CH2)nNHA oder (CH2JnNAA1, Ar unsubstituiertes oder ein-, zwei-, drei-, vier- oder fünffach durch A, HaI, (CH2)nOA, (CH2)nOH, (CH2)nCN, 15 SA, SOA, SO2A, NO2, C≡CH, (CH2)nCOOH, CHO,(CH 2 ) n NH 2 , (CH 2 ) n NHA or (CH 2 J n NAA 1 , Ar unsubstituted or one, two, three, four or five times by A, Hal, (CH 2 ) n OA , (CH 2 ) n OH, (CH 2 ) n CN, 15 SA, SOA, SO 2 A, NO 2 , C≡CH, (CH 2 ) n COOH, CHO,
(CH2)nCOOA, CONH2, CONHA, CONAA1, NHCOA,(CH 2 ) n COOA, CONH 2 , CONHA, CONAA 1 , NHCOA,
CH(OH)A, (CH2)nNH2, (CH2)nNHA, (CH2JnNAA1,CH (OH) A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 J n NAA 1 ,
(CH2)nNAAr1, O(CH2)nHet1, (CH2)nHet1, COO(CH2)nAr1,(CH 2 ) nNAAr 1 , O (CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO (CH 2 ) n Ar 1 ,
(CH2)nNHSO2A, (CH2)nOAr1, O(CH2)nAr1, pn(CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 , O (CH 2 ) n Ar 1 , pn
SO2NH(CH2)nNH2, SO2NH2, SO2NHA, SO2NAA1,SO 2 NH (CH 2 ) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA 1 ,
CONHAr1, CONH(CH2)nCOOA, CONH(CH2)nCOOH, NHCO(CH2)nCOOA, NHCO(CH2)nCOOH, CONH(CH2)nNH2, CONH(CH2)nNHA, CONH(CH2)nNAA\CONHAr 1 , CONH (CH 2 ) n COOA, CONH (CH 2 ) n COOH, NHCO (CH 2 ) n COOA, NHCO (CH 2 ) n COOH, CONH (CH 2 ) n NH 2 , CONH (CH 2 ) n NHA, CONH (CH 2 ) n NAA \
25 CONH(CH2)nCN, NHCOHet, SO2Het, COHet und/oder25 CONH (CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and / or
(CH2)nCH(NH2)COOH substituiertes Phenyl, Naphthyl, Tetrahydronaphthyl oder Biphenyl, Ar1 unsubstituiertes oder ein-, zwei-, drei-, vier- oder(CH 2 ) n CH (NH 2 ) COOH substituted phenyl, naphthyl, tetrahydronaphthyl or biphenyl, Ar 1 unsubstituted or mono-, di-, tri-, tetra- or
30 fünffach durch A, HaI und/oder OA substituiertes 30 five-fold substituted by A, Hal and / or OA
Phenyl,phenyl,
Het unsubstituiertes oder ein-, zwei- oder dreifach durchHet unsubstituted or one, two or three times
HaI, Phenyl, A, (CH2)nOH, (CH2JnOA, COOH, COOA1 COOBenzyl, CN, COA1 CHO, (CH2JnNH2, (CH2)nNHA,Hal, phenyl, A, (CH 2 ) n OH, (CH 2 J n OA, COOH, COOA 1 COOBenzyl, CN, COA 1 CHO, (CH 2 J n NH 2 , (CH 2 ) n NHA,
OΌ (CH2)nNAA" und/oder =0 (Carbonylsauerstoff) substituiertes Pyridyl, Pyrimidinyl, Furyl, Thienyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Benzothiazolyl, Benzo[1 ,4]- dioxanyl, Chinolyl, Isochinolyl, Chinazolinyl, OΌ (CH 2 ) n NAA "and / or = O (carbonyl oxygen) substituted pyridyl, pyrimidinyl, furyl, thienyl, Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, benzo [1,4] dioxanyl, quinolyl, isoquinolyl, quinazolinyl,
Benzimidazolyl, Indazolyl, Indolyl, 1 ,3-Dihydro- isoindolyl, Benzofuranyl, Dihydrobenzofuranyl,Benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzofuranyl,
Benzo[1 ,3]dioxolyl, Piperazinyl, Pyrazinyl, Pyridazinyl, Morpholinyl, Azepanyl, Pyrrolidinyl oder Piperidinyl, Het1 unsubstituiertes oder einfach durch =0 (Carbonylsauerstoff) substituiertes Morpholinyl,Benzo [1, 3] dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, pyrrolidinyl or piperidinyl, Het 1 unsubstituted or monosubstituted by = 0 (carbonyl oxygen) morpholinyl,
Piperidinyl oder Pyrrolidinyl,Piperidinyl or pyrrolidinyl,
A, A' jeweils unabhängig voneinander unverzweigtes oder verzweigtes Alkyl mit 1-6 C-Atomen, worin 1-2 CH2- Gruppen durch O, NH und/oder NMe und/oder auch 1-5A, A 'each independently of one another are unbranched or branched alkyl having 1-6 C atoms, in which 1-2 CH.sub.2 groups are represented by O, NH and / or NMe and / or also 1-5
H-Atome durch F, OH und/oder Cl ersetzt sein können, oder cyclisches Alkyl mit 3-8 C-Atomen, worin 1-3 H-Atome durch OH ersetzt sein können, m 0, 1 oder 2, n 0, 1 oder 2, bedeuten, sowie deren Salze. H atoms may be replaced by F, OH and / or Cl, or cyclic alkyl having 3-8 C atoms, in which 1-3 H atoms may be replaced by OH, m is 0, 1 or 2, n is 0, 1 or 2, and their salts.
EP08773474.5A 2007-07-13 2008-06-16 Quinazolinamide derivatives useful for the treatment of tumour diseases Not-in-force EP2164833B1 (en)

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DE102007032739A DE102007032739A1 (en) 2007-07-13 2007-07-13 Chinazolinamidderivate
PCT/EP2008/004846 WO2009010139A2 (en) 2007-07-13 2008-06-16 Quinazolinamide derivatives

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